This study is based on wireless optogenetic technology,utilizing the CRY2/CIB1 photosensitive system to achieve spatiotemporal control of PD-L1 expression.In vitro experiments showed that the surface PD-L1 positivity ...This study is based on wireless optogenetic technology,utilizing the CRY2/CIB1 photosensitive system to achieve spatiotemporal control of PD-L1 expression.In vitro experiments showed that the surface PD-L1 positivity rate of cells increased from 28.6±3.1%to 67.3±5.4%(P<0.001).In animal experiments,the terminal tumor volume in the light exposure group was 450±90 mm3,with a tumor inhibition rate of approximately 49.4%(P<0.001),and the median survival was extended to 32 days(compared to 24 days in the control group,P=0.004).Immunological tests revealed a significant increase in CD8+T cell infiltration(112±18 vs 52±10 cells/HPF,P<0.01),a 30%decrease in the proportion of Tregs(P<0.05),and an increase in the M1/M2 macrophage ratio to 1.8.The results suggest that the wireless optogenetic system can not only precisely regulate PD-L1 but also remodel the tumor immune microenvironment,providing a new approach for precise immunotherapy of GBM.展开更多
Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the util...Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography(PET/CT)remains limited.This investigation involved the synthesis of[18F]AlF-NOTA-PCP2,which is a novel peptide-based radiolabeled tracer that targets PD-L1,and evaluated its imaging capabilities in orthotopic glioblastoma(GBM)models.Using this tracer,we could noninvasively monitor radiation-induced PD-L1 changes in GBM.[18F]AlF-NOTA-PCP2 exhibited high radiochemical purity(>95%)and stability up to 4 h after synthesis.It demonstrated specific,high-affinity binding to PD-L1 in vitro and in vivo,with a dissociation constant of 0.24 nM.PET/CT imaging,integrated with contrast-enhanced magnetic resonance imaging,revealed significant accumulation of[18F]AlF-NOTA-PCP2 in orthotopic tumors,correlating with blood-brain barrier disruption.After radiotherapy(15 Gy),[18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51%±0.73%to 12.04%±1.43%,indicating enhanced PD-L1 expression consistent with immunohistochemistry findings.Fractionated radiation(5 Gy×3)further amplified PD-L1 upregulation(13.9%±1.54%ID/cc)compared with a single dose(11.48%±1.05%ID/cc).Taken together,[18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.展开更多
Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative bre...Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.展开更多
Objective:To investigate the correlation and overlaps between PD-L1 expression and classical genomic aberrations in Chinese lung adenocarcinoma(LADC)patients.Methods:We reviewed 428 consecutive,surgically resected cas...Objective:To investigate the correlation and overlaps between PD-L1 expression and classical genomic aberrations in Chinese lung adenocarcinoma(LADC)patients.Methods:We reviewed 428 consecutive,surgically resected cases of LADC from October 2015 to December 2016 from our center.PD-L1 expression was evaluated based on tumor proportion score(TPS).Correlation and co-occurrence of PD-L1 expression level with those of classical driver genes,such as EGFR,ALK,ROS-1,and KRAS and with clinical variables and disease-free survival(DFS)were analyzed.Results:Seventy of the 428 cases(16.4%)showed TPS≥1%,and 21 cases(4.9%)showed TPS≥50%.PD-L1 positive expression was significantly associated with male gender,smoking,advanced TNM stage,and solid histologic subtype.Both TPS≥1% and ≥50%were correlated with the absence of an EGFR mutation(P<0.001)and the presence of ALK rearrangement(P=0.024).KRAS mutation was associated with TPS≥50%(P=0.035).PD-L1 positivity commonly overlapped with the alterations of classical driver oncogenes(58.5%with TPS≥1% and 42.9% with TPS≥50%).Approximately three-quarters of PD-L1 positive cases co-occurred with classical therapeutic-gene aberrations in cases with stage III/IV cancer or cancer progression.LADC could be divided into four subgroups based on the expression profile of current routine biomarkers for potential therapeutic strategies.Conclusions:PD-L1 expression is not only closely correlated with classic gene alterations but also commonly overlaps with the aberrations of classical driver oncogenes in Chinese LADC patients.These findings provide a useful overview of clinical strategies that rely on the profile of routinely used molecular biomarkers.展开更多
Objective：The programmed cell death-1 receptor/programmed cell death-1 ligand （PD-1/PD-L1） pathway plays a crucial role in tumor evasion from host immunity.This study was designed to evaluate the association betwee...Objective：The programmed cell death-1 receptor/programmed cell death-1 ligand （PD-1/PD-L1） pathway plays a crucial role in tumor evasion from host immunity.This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer.Methods：Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study.Circulating PD-L1 expression was tested by enzymelinked immunosorbent assay （ELISA）.The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically.Results：Expression of PD-L1 in advanced gastric cancer patients was significandy up-regulated compared with health people （P=0.006）.The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis （P=0.026 and P=0.041,respectively）.Although we didn＇t find significant difference in all advanced gastric cancer patients with different PD-L1 expression,the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients （65.6％ vs.44.7％,P=0.028）.Conclusions：PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.展开更多
Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critica...Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critical role in EGFR-driven lung tumors.This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer(NSCLC).The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Methods:In total,73 patients with surgically resected NSCLC and EGFR mutations were identified.PD-L1 expression and CD8+tumor-infiltrating lymphocyte(TIL)density were assessed by immunohistochemistry.A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen(26.0%)patients were positive for PD-L1 expression,which was significantly associated with concomitant KRAS mutation(P=0.020)and marginally associated with higher CD8+TILs density(P=0.056).Positive PD-L1 expression was associated with markedly inferior overall survival(OS)in multivariate analysis(P=0.032).The combination of PD-L1 and CD8+TILs expression could be used to stratify the population into three groups with distinct prognoses.A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS[hazard ratio(HR)=0.90;95%confidence interval(CI),0.42–1.38]or progression-free survival(HR=1.03;95 CI,0.73–1.33)in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs.Conclusions:PD-L1 expression tended to correlate with CD8+TIL expression,concomitant KRAS mutation,and poor survival in surgically resected EGFR-mutant NSCLC.PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.展开更多
Despite advances in immunotherapy for the treatment of cancers,not all patients can benefit from programmed cell death ligand 1(PD-L1)immune checkpoint blockade therapy.Anti-PD-L1 therapeutic effects reportedly correl...Despite advances in immunotherapy for the treatment of cancers,not all patients can benefit from programmed cell death ligand 1(PD-L1)immune checkpoint blockade therapy.Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level;hence,accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects.Therefore,based on the high affinity antibody Nb109,a new site-specifically radiolabeled tracer,^(68)Ga-NODA-cysteine,aspartic acid,and valine(CDV)-Nb109,was designed and synthesized to accurately monitor PD-L1 expression.The tracer ^(68)Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95%and radiochemical purity of 97%.It showed high affinity for PD-L1 with a dissociation constant of 12.34±1.65 nM.Both the cell uptake assay and positron emission tomography(PET)imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells.Meanwhile,dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression,allowing timely interventional immunotherapy.In conclusion,this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.展开更多
Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abn...Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.展开更多
Background The association between the expression of programmed cell death 1(PD-1) or its ligand [programmed cell death ligand-1(PD-L1)] and colorectal cancer(CRC) survival rates remains unclear. Thus, we conducted a ...Background The association between the expression of programmed cell death 1(PD-1) or its ligand [programmed cell death ligand-1(PD-L1)] and colorectal cancer(CRC) survival rates remains unclear. Thus, we conducted a meta-analysis to investigate the prognostic value of PD-L1 expression in CRC patients.Methods All eligible studies related to evaluation of PD-L1 expression and survival of CRC patients were searched in PubMed, Medline, Cochrane library, and the EMBASE database. Hazard ratios(HRs) and 95% confidence intervals(CI) of overall survival(OS) were examined to assess the effect of PD-L1 expression on the survival of CRC patients. The outcomes of this meta-analysis were synthesized based on randomeffects model. Subgroup analyses were also performed. Results Seven studies, wherein OS data were stratified according to the expression status of PD-L1, were analyzed. CRC patients showing positive PD-L1 expression were associated with significantly poorer prognoses in terms of overall survival, compared with those displaying negative PD-L1 expression(HR = 1.43, 95% CI: 1.07–1.92; P = 0.02). In the subgroup analyses, H-scores as well as the percentage of stained cells indicated that PD-L1 expression was significantly associated with poor prognosis(HR = 1.90, 95% CI: 1.38–2.62, P < 0.01; HR = 1.81, 95% CI: 1.08–3.03, P = 0.02). Immunohistochemical staining, utilizing a rabbit anti-PD-L1 antibody, revealed significantly superior survival in the PD-L1 negative group compared with the PD-L1 positive expression group(HR = 1.92; 95% CI, 1.40-2.63; P < 0.01). Moreover, PD-L1 expression was significantly associated with poor prognosis when polyclonal antibodies were used(HR = 1.84; 95% CI, 1.30–2.61; P < 0.01). Conclusion Our meta-analysis indicated that PD-L1 expression status is a significant prognostic factor for CRC patients. Positive PD-L1 expression was associated with worse CRC survival. Evaluation via different immunohistochemistry based techniques may partly account for the contradictory results. Therefore, further investigative studies using larger sample sizes are felt to be needed to elucidate the prognostic value of PD-L1 expression in CRC patients.展开更多
BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment.The expression of CD155 is correlated with the prognosis and pathological features of brea...BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment.The expression of CD155 is correlated with the prognosis and pathological features of breast cancer.AIM To investigate the expression status of CD155 and the association with exhausted CD4+helper and CD8+cytotoxic tumor infiltrating lymphocytes(TILs)and PD-L1 in the breast cancer microenvironment.METHODS One hundred and twenty-six breast cancer patients with invasive ductal breast cancer were consecutively recruited into this study.Immunohistochemistry was used to detect the expression CD155,PD-L1 and PD-1 on tumor-infiltrating immune cells and tumor cells in the microenvironment.RESULTS The proportion of patients with CD155 expression was higher in triple negative breast cancer(72.7%)than in Luminal A patients(22.2%,P<0.05).Patients with positive CD155 expression had a higher percentage of CD4+/PD-1+helper TILs(30%)than patients with negative CD155 expression(21%,P<0.05).Patients with positive CD155 expression also had higher cell counts of exhausted CD4+TILs[47 vs 20/high-power fields(HPF)]and unexhausted CD8+TILs(30 vs 17/HPF)than patients with negative expression(P<0.05).CD155 expression was correlated with increased PD-L1 expression in immune cells,0.8%and 0.02%immune cells expressed PD-L1 in patients with positive and negative CD155 expression,respectively(P<0.05).CONCLUSION CD155 was related to an inhibitory immune breast cancer microenvironment.CD155 was associated with a high proportion of exhausted CD4+and unexhausted CD8+TILs and high PD-L1 expression in immune cells.展开更多
Objective:To explore the relationship between multimodal imaging features and metabolic parameters derived from^(18)F-FDG PET/CT and the mutation status of epidermal growth factor receptor(EGFR)and the expression of p...Objective:To explore the relationship between multimodal imaging features and metabolic parameters derived from^(18)F-FDG PET/CT and the mutation status of epidermal growth factor receptor(EGFR)and the expression of programmed cell death ligand 1(PD-L1)in non-small cell lung cancer(NSCLC),so as to provide objective evidence for clinical screening of targeted therapy and immunotherapy beneficiaries.Methods:Data of NSCLC patients who underwent^(18)F-FDG PET/CT scans,EGFR mutation and PD-L1 expression tests with confirmed pathological results were collected.The differences of PET/CT morphological characteristics and metabolic parameters between the EGFR mutation and the wild group,and between the PD-L1 expression positive and the negative group were analyzed.Univariate and multivariate logistic regression analyses were used to test the correlation between clinical and PET/CT parameters and EGFR mutation and PD-L1 expression status.Results:MTV(P=0.01)and TLG(P=0.00)values of EGFR mutant patients were statistically lower than those of wild type patients.Univariate and multivariate logistic analysis showed that age(P=0.03),smoking history(P=0.00)and MTV(P=0.00)were independent risk factors for EGFR mutation.The positive expression of PD-L1 in stageⅢ/Ⅳgroup was significantly higher than that in stageⅠ/ⅡGroup(P=0.01),but there was no significant difference in different age,gender,smoking history,SUVmax,MTV,TLG,LDH and CEA groups.Logistic univariate analysis showed that only stage was associated with the positive expression rate of PD-L1(P=0.01).There was no significant correlation between PET/CT parameters and PD-L1 status.Conclusion:PET/CT metabolic parameters MTV,age and smoking history are independent predictors of EGFR mutation,which is expected to provide objective evidence for clinical screening of targeted treatment beneficiaries;however,PET/CT metabolic parameters are not good in predicting PD-L1 protein expression,which needs to be further verified by large sample.展开更多
Small cell lung cancer is an invasive neuroendocrine carcinoma with early metastasis potential. It tends to grow rapidly and metastasize early, with the majority of patients diagnosed as advanced stage small cell lung...Small cell lung cancer is an invasive neuroendocrine carcinoma with early metastasis potential. It tends to grow rapidly and metastasize early, with the majority of patients diagnosed as advanced stage small cell lung cancer (ES-SCLC). Systemic treatment consisting of platinum drugs and etoposide chemotherapy is the main treatment method, although the objective effective rate of this combination is 60% - 80%. However, most SCLC patients experience disease progression shortly after initial treatment, with a median overall survival of 10 months. There are few second-line treatment drugs available, and immunotherapy using checkpoint inhibitors has completely changed the treatment of many cancer types. Adding immune checkpoint inhibitors (ICI) to conventional chemotherapy as first-line treatment can improve the survival rate of widespread small cell lung cancer (ES-SCLC), but so far, there are no definitive factors to determine patients who are more likely to benefit from immunotherapy. This review summarizes the results of immunotherapy trials for small cell lung cancer. And a review was conducted on the predictive factors of these trials, with special emphasis on the expression of PD-L1 in small cell lung cancer to determine its clinical value.展开更多
Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherap...Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P < 0.05), T stage (T3 vs T4: P = 0.039), and MSH3 expression was related to T stage (P < 0.05). Besides, both MSH2 expression (P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.展开更多
Background Neurofibromatosis type 1(NF1)is an autosomal dominant inherited disorder.It can affect multiple systems of the body and cause severe disfigurement and discomfort in these patients.There are two types of neu...Background Neurofibromatosis type 1(NF1)is an autosomal dominant inherited disorder.It can affect multiple systems of the body and cause severe disfigurement and discomfort in these patients.There are two types of neurofibromas,named cutaneous and plexiform neurofibromas.The latter type may transform into malignant peripheral nerve sheath tumors(MPNSTs).Surgical resection is difficult to perform owing to the complex tissue structure of neurofibromas;therefore,it is necessary to develop novel and effective therapies for the treatment of these tumors.Programmed cell death protein 1(PD-1)/programmed cell death-ligand 1(PD-L1)-related immune checkpoint inhibitors have been proven effective for various cancers,and the positive expression of PD-L1 and tumor-infiltrating lymphocytes(TILs)has been recognized as a biomarker for the response to immune checkpoint therapy.Methods We conducted immunohistochemistry(IHC)staining to detect PD-L1 expression in plexiform neurofibroma and MPNST tissue samples.Reverse transcription-polymerase chain reaction(RT-PCR)and western blotting were performed to detect PD-L1 and PD-1 expression in MPNST cell lines.IHC staining was used to show immune cell infiltration in NF1 and MPNST tissues.Results IHC staining showed PD-L1 positive expression in neurofibromas and MPNST tumor tissues.In addition,qPCR and western blotting showed high expression of PD-L1 in MPNST tumor cells.IHC staining revealed that aberrant T lymphocytes infiltrated the plexiform neurofibroma and MPNST tumor tissues.Conclusion These results indicate that immune checkpoint mechanisms may play a pivotal role in the development of NF1-related tumors,and immune checkpoint inhibitors may be effective for managing neurofibromas and MPNSTs.Combined therapy with other molecular agents may be explored in the future.展开更多
Objectives:While programmed cell death 1(PD-1)inhibitors have improved cancer treatment,the function and mechanisms of programmed cell death ligand 1(PD-L1),particularly when expressed by cancer cells,remain unclear.T...Objectives:While programmed cell death 1(PD-1)inhibitors have improved cancer treatment,the function and mechanisms of programmed cell death ligand 1(PD-L1),particularly when expressed by cancer cells,remain unclear.This study aims to explore the role of PD-L1 within breast cancer cells and identify key targets for future immunotherapy.Methods:RNA-seq was performed on breast cancer cells with silenced PD-L1 to screen for differentially expressed genes,followed by bioinformatics analysis.Clinical specimens from breast cancer patients undergoing primary surgery without preoperative treatment were collected,along with in vitro analysis to validate the potential mechanism.Results:RNA-seq data revealed a significant positive correlation between Ecto-5′-nucleotidase(NT5E)expression and PD-L1.Bioinformatics analysis corroborated this positive correlation.Immunohistochemistry staining demonstrated higher NT5E expression associated with increased lymph node metastasis.High expression of the NT5E gene was associated with poor overall survival(OS)in breast cancer patients,as determined by KM plotter analysis.Following PD-L1 gene silencing by siRNA in breast cancer cells,NT5E mRNA and protein expression significantly decreased.Conversely,no significant changes were observed in PD-L1 expression after NT5E gene silencing.In vitro experiments confirmed that cancer cell proliferation and metastasis abilities were significantly reduced by either PD-L1 or NT5E gene down-regulation.Western blotting demonstrated that PD-L1 expressed by cancer cells regulates NT5E expression through the MAPK/ERK signaling pathway.Conclusion:This study proposes a potential mechanism wherein tumor-expressing PD-L1 regulates NT5E through the MAPK/ERK pathway.Downregulation of PD-L1 or NT5E can significantly inhibit the proliferation and metastatic ability of cancer cells,potentially providing practical therapeutic targets and prognostic markers for combined PD-L1 immunotherapy in breast cancer.展开更多
Objective:To investigate the correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer,providing new therapeutic targets for immunotherapy in gastric cancer.Methods:This study selected gastric cancer pati...Objective:To investigate the correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer,providing new therapeutic targets for immunotherapy in gastric cancer.Methods:This study selected gastric cancer patients who were diagnosed and treated at our hospital from October 2022 to October 2024 as the research subjects.Based on the patients’PD-L1 examination results,they were divided into a positive group and a negative group.General patient data were collected,and qPCR and WB experiments were used to detect the levels of CMTM6 and miRNA in the patients.Univariate analysis was conducted to identify factors influencing PD-L1 expression,and variables with p<0.05 were included in multivariate logistic regression analysis to clarify the correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer.Results:A total of 118 patients were included in this study,with 75 patients in the positive group and 43 patients in the negative group.Univariate analysis revealed that TNM stage,miRNA,and CMTM6 showed statistical significance in data comparison(p<0.05).These variables were then included in multivariate logistic regression analysis,which found that TNM stage(OR=2.849,95%CI:2.227-3.425),miRNA(OR=3.038,95%CI:2.968-3.509),and CMTM6(OR=3.185,95%CI:2.995-3.810)all exhibited a positive correlation with PD-L1 expression in gastric cancer.Conclusion:There is a certain correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer.As miRNA and CMTM6 levels increase,the positive rate of PD-L1 examination in patients also rises,warranting clinical attention.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)are effective cancer treatments;however,a significant proportion of colorectal cancer(CRC)patients exhibit limited re-sponses to ICI therapy.KAT6A has been strongly associa...BACKGROUND Immune checkpoint inhibitors(ICIs)are effective cancer treatments;however,a significant proportion of colorectal cancer(CRC)patients exhibit limited re-sponses to ICI therapy.KAT6A has been strongly associated with cancer initiation and progression.AIM To examine the role of KAT6A in CRC progression and immune evasion.METHODS The functional role of KAT6A was evaluated through genetic knockdown,pharmacological inhibition(WM-3835),and CRISPR/dCas9-mediated epigenetic editing in CRC cells.T cell-mediated apoptosis was assessed using co-culture models,and H3K23pr was measured via chromatin immunoprecipitation assays.PD-L1 expression at mRNA and protein levels was analyzed under KAT6A knockdown conditions.RESULTS KAT6A suppression reduced CRC cell proliferation,invasion,and migration.Pharmacological or epigenetic disruption of KAT6A phenocopied these effects,with dose-dependent reductions in H3K23pr(28.4%residual at 10μM)and PD-L1 expression.KAT6A knockdown enhanced T cell-mediated apoptosis,evidenced by increased expression of granzyme B and perforin.Mechanistically,KAT6A loss decreased H3K23pr and reduced RNA polymerase II occupancy on the PD-L1 promoter,leading to suppressed PD-L1 transcription.CRISPR/dCas9-mediated H3K23pr editing at the PD-L1 promoter directly modulated immune evasion,confirming its causal role.Overexpression of PD-L1 mitigated the inhibitory effects of KAT6A knockdown on CRC progression and immune evasion.CONCLUSION KAT6A drives CRC progression and immune evasion by promoting histone H3 propionylation to epigenetically activate PD-L1 expression.Targeting KAT6A or its downstream H3K23pr-PD-L1 axis represents a promising therapeutic strategy to overcome ICI resistance in CRC.展开更多
BACKGROUND ANAPC1,a key regulator of the ubiquitination in tumour development,has not been thoroughly studied in hepatocellular carcinoma(HCC).AIM To elucidate the expression of ANAPC1 in HCC and its potential regulat...BACKGROUND ANAPC1,a key regulator of the ubiquitination in tumour development,has not been thoroughly studied in hepatocellular carcinoma(HCC).AIM To elucidate the expression of ANAPC1 in HCC and its potential regulatory mechanism related to ubiquitination.METHODS Bulk RNA(RNA sequencing and microarrays),immunohistochemistry(IHC)tissues,and single-cell RNA sequencing(scRNA-seq)data were integrated to comprehensively investigate ANAPC1 expression in HCC.Clustered regularly interspaced short palindromic repeats analysis was performed to assess growth in HCC cell lines following ANAPC1 knockout.Enrichment analyses were conducted to explore the functions of ANAPC1.ScRNA-seq data was used to examine the cell cycle and metabolic levels.CellChat analysis was applied to investigate the interactions between ANAPC1 and different cell types.The relationship between ANAPC1 expression and drug concentration was analyzed.RESULTS ANAPC1 messenger RNA was found to be upregulated in bulk RNA,IHC tissues samples and malignant hepatocytes.The proliferation of JHH2 cell lines was most significantly inhibited after ANAPC1 knockdown.In biological pathways,the development of HCC was found to be linked to the regulation of ubiquitin-mediated proteolysis.Additionally,scRNA-seq results indicated that highly expressed ANAPC1 was in the G2/M phase,with increased glycolysis/gluconeogenesis activity.A CellChat analysis showed that ANAPC1 was associated with the regulation of the migration inhibitory factor-(cluster of differentiation 74+C-X-C chemokine receptor type 4)pathway.Higher ANAPC1 expression correlated with stronger effects of sorafenib,dasatinib,ibrutinib,lapatinib,nilotinib and afatinib.CONCLUSION The high expression level of ANAPC1 may regulate the cell cycle and metabolic levels of HCC through the ubiquitination-related pathway,thereby promoting disease progression.展开更多
文摘This study is based on wireless optogenetic technology,utilizing the CRY2/CIB1 photosensitive system to achieve spatiotemporal control of PD-L1 expression.In vitro experiments showed that the surface PD-L1 positivity rate of cells increased from 28.6±3.1%to 67.3±5.4%(P<0.001).In animal experiments,the terminal tumor volume in the light exposure group was 450±90 mm3,with a tumor inhibition rate of approximately 49.4%(P<0.001),and the median survival was extended to 32 days(compared to 24 days in the control group,P=0.004).Immunological tests revealed a significant increase in CD8+T cell infiltration(112±18 vs 52±10 cells/HPF,P<0.01),a 30%decrease in the proportion of Tregs(P<0.05),and an increase in the M1/M2 macrophage ratio to 1.8.The results suggest that the wireless optogenetic system can not only precisely regulate PD-L1 but also remodel the tumor immune microenvironment,providing a new approach for precise immunotherapy of GBM.
基金support from the National Natural Science Foundation of China(Grant Nos.:82272751 and 82202958)the Natural Science Foundation of Shandong,China(Grant No.:ZR2021LSW002)+6 种基金the Science and Technology Program of Jinan,China(Grant Nos.:202225019 and 202225013)to Man Huthe Shandong Postdoctoral Innovation Program,China(Grant No.:SDCX-ZG-202302011)Beijing Science and Technology Innovation Medical Development Foundation,China(Grant No.:KC2023-JX-0288-BQ26)to Yong Wangthe Natural Science Foundation of China(Grant No.:NSFC82303676)the Natural Science Foundation of Shandong(Grant No.:ZR2023QH208)the China Postdoctoral Science Foundation(Grant No.:2023M732125)the Taishan Scholar Project Special Fund(Grant No.:tsqn202312368)to Kewen He.
文摘Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography(PET/CT)remains limited.This investigation involved the synthesis of[18F]AlF-NOTA-PCP2,which is a novel peptide-based radiolabeled tracer that targets PD-L1,and evaluated its imaging capabilities in orthotopic glioblastoma(GBM)models.Using this tracer,we could noninvasively monitor radiation-induced PD-L1 changes in GBM.[18F]AlF-NOTA-PCP2 exhibited high radiochemical purity(>95%)and stability up to 4 h after synthesis.It demonstrated specific,high-affinity binding to PD-L1 in vitro and in vivo,with a dissociation constant of 0.24 nM.PET/CT imaging,integrated with contrast-enhanced magnetic resonance imaging,revealed significant accumulation of[18F]AlF-NOTA-PCP2 in orthotopic tumors,correlating with blood-brain barrier disruption.After radiotherapy(15 Gy),[18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51%±0.73%to 12.04%±1.43%,indicating enhanced PD-L1 expression consistent with immunohistochemistry findings.Fractionated radiation(5 Gy×3)further amplified PD-L1 upregulation(13.9%±1.54%ID/cc)compared with a single dose(11.48%±1.05%ID/cc).Taken together,[18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.
基金the projects of the National Key Research and Development Program(No.2021YFA0716702)the National Natural Science Foundation of China(Nos.61805122,22022404 and 22074050)+5 种基金Green Industry Science and Technology Leading Project of Hubei University of Technology(No.XJ2021003301)the National Natural Science Foundation of Hubei Province(No.2022CFA033)supported by Chinese Society of Clinical Oncology(CSCO)supported by Jiangsu Hengrui Cancer Research Foundation(No.YHR2019–0325)supported by the Fundamental Research Funds for the Central Universities(No.CCNU22QN007)supported by the Opening Fund from the Jiangsu Key Laboratory of Medical Optics,Suzhou Institute of Biomedical Engineering and Technology(No.JKLMO202203)supported by the Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science,MO(No.M2022–5).
文摘Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.
基金supported by the National Natural Science Foundation of China (Grant No. 81871860)
文摘Objective:To investigate the correlation and overlaps between PD-L1 expression and classical genomic aberrations in Chinese lung adenocarcinoma(LADC)patients.Methods:We reviewed 428 consecutive,surgically resected cases of LADC from October 2015 to December 2016 from our center.PD-L1 expression was evaluated based on tumor proportion score(TPS).Correlation and co-occurrence of PD-L1 expression level with those of classical driver genes,such as EGFR,ALK,ROS-1,and KRAS and with clinical variables and disease-free survival(DFS)were analyzed.Results:Seventy of the 428 cases(16.4%)showed TPS≥1%,and 21 cases(4.9%)showed TPS≥50%.PD-L1 positive expression was significantly associated with male gender,smoking,advanced TNM stage,and solid histologic subtype.Both TPS≥1% and ≥50%were correlated with the absence of an EGFR mutation(P<0.001)and the presence of ALK rearrangement(P=0.024).KRAS mutation was associated with TPS≥50%(P=0.035).PD-L1 positivity commonly overlapped with the alterations of classical driver oncogenes(58.5%with TPS≥1% and 42.9% with TPS≥50%).Approximately three-quarters of PD-L1 positive cases co-occurred with classical therapeutic-gene aberrations in cases with stage III/IV cancer or cancer progression.LADC could be divided into four subgroups based on the expression profile of current routine biomarkers for potential therapeutic strategies.Conclusions:PD-L1 expression is not only closely correlated with classic gene alterations but also commonly overlaps with the aberrations of classical driver oncogenes in Chinese LADC patients.These findings provide a useful overview of clinical strategies that rely on the profile of routinely used molecular biomarkers.
文摘Objective：The programmed cell death-1 receptor/programmed cell death-1 ligand （PD-1/PD-L1） pathway plays a crucial role in tumor evasion from host immunity.This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer.Methods：Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study.Circulating PD-L1 expression was tested by enzymelinked immunosorbent assay （ELISA）.The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically.Results：Expression of PD-L1 in advanced gastric cancer patients was significandy up-regulated compared with health people （P=0.006）.The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis （P=0.026 and P=0.041,respectively）.Although we didn＇t find significant difference in all advanced gastric cancer patients with different PD-L1 expression,the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients （65.6％ vs.44.7％,P=0.028）.Conclusions：PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.
基金supported in part by grants from the National Natural Science Foundation of China(Grant No.81672286,81772467 and 81874036)“Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(Grant No.16SG18)the Chronic Diseases Program of Shanghai Shen Kang Pharmaceutical Development Co.Ltd(Grant No.SHDC 12015314)
文摘Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critical role in EGFR-driven lung tumors.This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer(NSCLC).The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Methods:In total,73 patients with surgically resected NSCLC and EGFR mutations were identified.PD-L1 expression and CD8+tumor-infiltrating lymphocyte(TIL)density were assessed by immunohistochemistry.A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen(26.0%)patients were positive for PD-L1 expression,which was significantly associated with concomitant KRAS mutation(P=0.020)and marginally associated with higher CD8+TILs density(P=0.056).Positive PD-L1 expression was associated with markedly inferior overall survival(OS)in multivariate analysis(P=0.032).The combination of PD-L1 and CD8+TILs expression could be used to stratify the population into three groups with distinct prognoses.A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS[hazard ratio(HR)=0.90;95%confidence interval(CI),0.42–1.38]or progression-free survival(HR=1.03;95 CI,0.73–1.33)in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs.Conclusions:PD-L1 expression tended to correlate with CD8+TIL expression,concomitant KRAS mutation,and poor survival in surgically resected EGFR-mutant NSCLC.PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.
基金support from the National Natural Science Foundation of China(Grant No.:22076069)the Natural Science Foundation of Jiangsu Province(Grant No.:BK20201135)+1 种基金the Major Scientific Research Project of Jiangsu Commission of Health(Grant No.:ZDA2020007)the Science Technology and Development Project of Wuxi(Grant No.:Y20212013).
文摘Despite advances in immunotherapy for the treatment of cancers,not all patients can benefit from programmed cell death ligand 1(PD-L1)immune checkpoint blockade therapy.Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level;hence,accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects.Therefore,based on the high affinity antibody Nb109,a new site-specifically radiolabeled tracer,^(68)Ga-NODA-cysteine,aspartic acid,and valine(CDV)-Nb109,was designed and synthesized to accurately monitor PD-L1 expression.The tracer ^(68)Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95%and radiochemical purity of 97%.It showed high affinity for PD-L1 with a dissociation constant of 12.34±1.65 nM.Both the cell uptake assay and positron emission tomography(PET)imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells.Meanwhile,dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression,allowing timely interventional immunotherapy.In conclusion,this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.
基金supported by the Science&Technology Development Fund of Tianjin Education Commission for Higher Education,Tianjin,China(Grant No.2017KJ200)。
文摘Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.
基金Supported by the National Natural Science Foundation of China(No.81372396)Natural Science Foundation of Jiangsu Province(No.BK20141016 and BK20141017)
文摘Background The association between the expression of programmed cell death 1(PD-1) or its ligand [programmed cell death ligand-1(PD-L1)] and colorectal cancer(CRC) survival rates remains unclear. Thus, we conducted a meta-analysis to investigate the prognostic value of PD-L1 expression in CRC patients.Methods All eligible studies related to evaluation of PD-L1 expression and survival of CRC patients were searched in PubMed, Medline, Cochrane library, and the EMBASE database. Hazard ratios(HRs) and 95% confidence intervals(CI) of overall survival(OS) were examined to assess the effect of PD-L1 expression on the survival of CRC patients. The outcomes of this meta-analysis were synthesized based on randomeffects model. Subgroup analyses were also performed. Results Seven studies, wherein OS data were stratified according to the expression status of PD-L1, were analyzed. CRC patients showing positive PD-L1 expression were associated with significantly poorer prognoses in terms of overall survival, compared with those displaying negative PD-L1 expression(HR = 1.43, 95% CI: 1.07–1.92; P = 0.02). In the subgroup analyses, H-scores as well as the percentage of stained cells indicated that PD-L1 expression was significantly associated with poor prognosis(HR = 1.90, 95% CI: 1.38–2.62, P < 0.01; HR = 1.81, 95% CI: 1.08–3.03, P = 0.02). Immunohistochemical staining, utilizing a rabbit anti-PD-L1 antibody, revealed significantly superior survival in the PD-L1 negative group compared with the PD-L1 positive expression group(HR = 1.92; 95% CI, 1.40-2.63; P < 0.01). Moreover, PD-L1 expression was significantly associated with poor prognosis when polyclonal antibodies were used(HR = 1.84; 95% CI, 1.30–2.61; P < 0.01). Conclusion Our meta-analysis indicated that PD-L1 expression status is a significant prognostic factor for CRC patients. Positive PD-L1 expression was associated with worse CRC survival. Evaluation via different immunohistochemistry based techniques may partly account for the contradictory results. Therefore, further investigative studies using larger sample sizes are felt to be needed to elucidate the prognostic value of PD-L1 expression in CRC patients.
基金Supported by Beijing Municipal Committee of Science and Technology,No.Z181100001718090 and Z19110006619041Beijing Municipal Administration of Hospitals,No.PX2018029Beijing Shijitan Hospital,Capital Medical University,No.2017-KF01.
文摘BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment.The expression of CD155 is correlated with the prognosis and pathological features of breast cancer.AIM To investigate the expression status of CD155 and the association with exhausted CD4+helper and CD8+cytotoxic tumor infiltrating lymphocytes(TILs)and PD-L1 in the breast cancer microenvironment.METHODS One hundred and twenty-six breast cancer patients with invasive ductal breast cancer were consecutively recruited into this study.Immunohistochemistry was used to detect the expression CD155,PD-L1 and PD-1 on tumor-infiltrating immune cells and tumor cells in the microenvironment.RESULTS The proportion of patients with CD155 expression was higher in triple negative breast cancer(72.7%)than in Luminal A patients(22.2%,P<0.05).Patients with positive CD155 expression had a higher percentage of CD4+/PD-1+helper TILs(30%)than patients with negative CD155 expression(21%,P<0.05).Patients with positive CD155 expression also had higher cell counts of exhausted CD4+TILs[47 vs 20/high-power fields(HPF)]and unexhausted CD8+TILs(30 vs 17/HPF)than patients with negative expression(P<0.05).CD155 expression was correlated with increased PD-L1 expression in immune cells,0.8%and 0.02%immune cells expressed PD-L1 in patients with positive and negative CD155 expression,respectively(P<0.05).CONCLUSION CD155 was related to an inhibitory immune breast cancer microenvironment.CD155 was associated with a high proportion of exhausted CD4+and unexhausted CD8+TILs and high PD-L1 expression in immune cells.
基金This study was supported by Research and Cultivation Foundation of Hainan Medical College(No.HYPY2020022)Hainan Natural Science Foundation Youth fund(No.822QN482)Doctoral Research Fund Project of Hainan Cancer Hospital(No.2022BS04)。
文摘Objective:To explore the relationship between multimodal imaging features and metabolic parameters derived from^(18)F-FDG PET/CT and the mutation status of epidermal growth factor receptor(EGFR)and the expression of programmed cell death ligand 1(PD-L1)in non-small cell lung cancer(NSCLC),so as to provide objective evidence for clinical screening of targeted therapy and immunotherapy beneficiaries.Methods:Data of NSCLC patients who underwent^(18)F-FDG PET/CT scans,EGFR mutation and PD-L1 expression tests with confirmed pathological results were collected.The differences of PET/CT morphological characteristics and metabolic parameters between the EGFR mutation and the wild group,and between the PD-L1 expression positive and the negative group were analyzed.Univariate and multivariate logistic regression analyses were used to test the correlation between clinical and PET/CT parameters and EGFR mutation and PD-L1 expression status.Results:MTV(P=0.01)and TLG(P=0.00)values of EGFR mutant patients were statistically lower than those of wild type patients.Univariate and multivariate logistic analysis showed that age(P=0.03),smoking history(P=0.00)and MTV(P=0.00)were independent risk factors for EGFR mutation.The positive expression of PD-L1 in stageⅢ/Ⅳgroup was significantly higher than that in stageⅠ/ⅡGroup(P=0.01),but there was no significant difference in different age,gender,smoking history,SUVmax,MTV,TLG,LDH and CEA groups.Logistic univariate analysis showed that only stage was associated with the positive expression rate of PD-L1(P=0.01).There was no significant correlation between PET/CT parameters and PD-L1 status.Conclusion:PET/CT metabolic parameters MTV,age and smoking history are independent predictors of EGFR mutation,which is expected to provide objective evidence for clinical screening of targeted treatment beneficiaries;however,PET/CT metabolic parameters are not good in predicting PD-L1 protein expression,which needs to be further verified by large sample.
文摘Small cell lung cancer is an invasive neuroendocrine carcinoma with early metastasis potential. It tends to grow rapidly and metastasize early, with the majority of patients diagnosed as advanced stage small cell lung cancer (ES-SCLC). Systemic treatment consisting of platinum drugs and etoposide chemotherapy is the main treatment method, although the objective effective rate of this combination is 60% - 80%. However, most SCLC patients experience disease progression shortly after initial treatment, with a median overall survival of 10 months. There are few second-line treatment drugs available, and immunotherapy using checkpoint inhibitors has completely changed the treatment of many cancer types. Adding immune checkpoint inhibitors (ICI) to conventional chemotherapy as first-line treatment can improve the survival rate of widespread small cell lung cancer (ES-SCLC), but so far, there are no definitive factors to determine patients who are more likely to benefit from immunotherapy. This review summarizes the results of immunotherapy trials for small cell lung cancer. And a review was conducted on the predictive factors of these trials, with special emphasis on the expression of PD-L1 in small cell lung cancer to determine its clinical value.
文摘Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P < 0.05), T stage (T3 vs T4: P = 0.039), and MSH3 expression was related to T stage (P < 0.05). Besides, both MSH2 expression (P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.
基金This work was supported by the grants from the Youth Doctor Collaborative Innovation Team Project(QC201803)of Shanghai Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine,Shanghai Youth Top-Notch Talent Program(201809004)“Chenguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(19CG18)+3 种基金Science and Technology Commission of Shanghai Municipality(19JC1413)Shanghai Rising Star Program(20QA1405600)Innovative research team of high-level local universities in Shanghai(SSMU-ZDCX20180700)Shanghai Municipal Key Clinical Specialty(shslczdzk00901).
文摘Background Neurofibromatosis type 1(NF1)is an autosomal dominant inherited disorder.It can affect multiple systems of the body and cause severe disfigurement and discomfort in these patients.There are two types of neurofibromas,named cutaneous and plexiform neurofibromas.The latter type may transform into malignant peripheral nerve sheath tumors(MPNSTs).Surgical resection is difficult to perform owing to the complex tissue structure of neurofibromas;therefore,it is necessary to develop novel and effective therapies for the treatment of these tumors.Programmed cell death protein 1(PD-1)/programmed cell death-ligand 1(PD-L1)-related immune checkpoint inhibitors have been proven effective for various cancers,and the positive expression of PD-L1 and tumor-infiltrating lymphocytes(TILs)has been recognized as a biomarker for the response to immune checkpoint therapy.Methods We conducted immunohistochemistry(IHC)staining to detect PD-L1 expression in plexiform neurofibroma and MPNST tissue samples.Reverse transcription-polymerase chain reaction(RT-PCR)and western blotting were performed to detect PD-L1 and PD-1 expression in MPNST cell lines.IHC staining was used to show immune cell infiltration in NF1 and MPNST tissues.Results IHC staining showed PD-L1 positive expression in neurofibromas and MPNST tumor tissues.In addition,qPCR and western blotting showed high expression of PD-L1 in MPNST tumor cells.IHC staining revealed that aberrant T lymphocytes infiltrated the plexiform neurofibroma and MPNST tumor tissues.Conclusion These results indicate that immune checkpoint mechanisms may play a pivotal role in the development of NF1-related tumors,and immune checkpoint inhibitors may be effective for managing neurofibromas and MPNSTs.Combined therapy with other molecular agents may be explored in the future.
基金Provincial Natural Science Foundation J230016Provincial Natural Science Foundation H2023206441Hebei Province Major Science and Technology Support Program Project S&T Program of Hebei 242W7701Z.
文摘Objectives:While programmed cell death 1(PD-1)inhibitors have improved cancer treatment,the function and mechanisms of programmed cell death ligand 1(PD-L1),particularly when expressed by cancer cells,remain unclear.This study aims to explore the role of PD-L1 within breast cancer cells and identify key targets for future immunotherapy.Methods:RNA-seq was performed on breast cancer cells with silenced PD-L1 to screen for differentially expressed genes,followed by bioinformatics analysis.Clinical specimens from breast cancer patients undergoing primary surgery without preoperative treatment were collected,along with in vitro analysis to validate the potential mechanism.Results:RNA-seq data revealed a significant positive correlation between Ecto-5′-nucleotidase(NT5E)expression and PD-L1.Bioinformatics analysis corroborated this positive correlation.Immunohistochemistry staining demonstrated higher NT5E expression associated with increased lymph node metastasis.High expression of the NT5E gene was associated with poor overall survival(OS)in breast cancer patients,as determined by KM plotter analysis.Following PD-L1 gene silencing by siRNA in breast cancer cells,NT5E mRNA and protein expression significantly decreased.Conversely,no significant changes were observed in PD-L1 expression after NT5E gene silencing.In vitro experiments confirmed that cancer cell proliferation and metastasis abilities were significantly reduced by either PD-L1 or NT5E gene down-regulation.Western blotting demonstrated that PD-L1 expressed by cancer cells regulates NT5E expression through the MAPK/ERK signaling pathway.Conclusion:This study proposes a potential mechanism wherein tumor-expressing PD-L1 regulates NT5E through the MAPK/ERK pathway.Downregulation of PD-L1 or NT5E can significantly inhibit the proliferation and metastatic ability of cancer cells,potentially providing practical therapeutic targets and prognostic markers for combined PD-L1 immunotherapy in breast cancer.
文摘Objective:To investigate the correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer,providing new therapeutic targets for immunotherapy in gastric cancer.Methods:This study selected gastric cancer patients who were diagnosed and treated at our hospital from October 2022 to October 2024 as the research subjects.Based on the patients’PD-L1 examination results,they were divided into a positive group and a negative group.General patient data were collected,and qPCR and WB experiments were used to detect the levels of CMTM6 and miRNA in the patients.Univariate analysis was conducted to identify factors influencing PD-L1 expression,and variables with p<0.05 were included in multivariate logistic regression analysis to clarify the correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer.Results:A total of 118 patients were included in this study,with 75 patients in the positive group and 43 patients in the negative group.Univariate analysis revealed that TNM stage,miRNA,and CMTM6 showed statistical significance in data comparison(p<0.05).These variables were then included in multivariate logistic regression analysis,which found that TNM stage(OR=2.849,95%CI:2.227-3.425),miRNA(OR=3.038,95%CI:2.968-3.509),and CMTM6(OR=3.185,95%CI:2.995-3.810)all exhibited a positive correlation with PD-L1 expression in gastric cancer.Conclusion:There is a certain correlation between miRNA,CMTM6,and PD-L1 expression in gastric cancer.As miRNA and CMTM6 levels increase,the positive rate of PD-L1 examination in patients also rises,warranting clinical attention.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)are effective cancer treatments;however,a significant proportion of colorectal cancer(CRC)patients exhibit limited re-sponses to ICI therapy.KAT6A has been strongly associated with cancer initiation and progression.AIM To examine the role of KAT6A in CRC progression and immune evasion.METHODS The functional role of KAT6A was evaluated through genetic knockdown,pharmacological inhibition(WM-3835),and CRISPR/dCas9-mediated epigenetic editing in CRC cells.T cell-mediated apoptosis was assessed using co-culture models,and H3K23pr was measured via chromatin immunoprecipitation assays.PD-L1 expression at mRNA and protein levels was analyzed under KAT6A knockdown conditions.RESULTS KAT6A suppression reduced CRC cell proliferation,invasion,and migration.Pharmacological or epigenetic disruption of KAT6A phenocopied these effects,with dose-dependent reductions in H3K23pr(28.4%residual at 10μM)and PD-L1 expression.KAT6A knockdown enhanced T cell-mediated apoptosis,evidenced by increased expression of granzyme B and perforin.Mechanistically,KAT6A loss decreased H3K23pr and reduced RNA polymerase II occupancy on the PD-L1 promoter,leading to suppressed PD-L1 transcription.CRISPR/dCas9-mediated H3K23pr editing at the PD-L1 promoter directly modulated immune evasion,confirming its causal role.Overexpression of PD-L1 mitigated the inhibitory effects of KAT6A knockdown on CRC progression and immune evasion.CONCLUSION KAT6A drives CRC progression and immune evasion by promoting histone H3 propionylation to epigenetically activate PD-L1 expression.Targeting KAT6A or its downstream H3K23pr-PD-L1 axis represents a promising therapeutic strategy to overcome ICI resistance in CRC.
基金Co-first authors:Yu-Xing Tang 0000-0003-4382-4942Co-first authors:Wei-Zi Wu+8 种基金Corresponding author:Gang Chen,MD,Professor,Department of Pathology,The First Affiliated Hospital of Guangxi Medical University,No.6 Shuangyong Road,Nanning 530021,Guangxi Zhuang Autonomous Region,China.chengang@gxmu.edu.cn,0000-0003-2402-2987Co-corresponding authors:Yan-Ting ZhanSheng-Sheng Zhou,0000-0003-2414-460XDa-Tong Zeng,0000-0002-3338-4122Guang-Cai Zheng,0009-0001-5921-6688Rong-Quan He,0000-0002-7752-2080Di-Yuan Qin,0009-0003-3214-4762Wan-Ying Huang,0000-0002-8314-5963Yu-Lu Tang,0009-0004-0462-618X。
文摘BACKGROUND ANAPC1,a key regulator of the ubiquitination in tumour development,has not been thoroughly studied in hepatocellular carcinoma(HCC).AIM To elucidate the expression of ANAPC1 in HCC and its potential regulatory mechanism related to ubiquitination.METHODS Bulk RNA(RNA sequencing and microarrays),immunohistochemistry(IHC)tissues,and single-cell RNA sequencing(scRNA-seq)data were integrated to comprehensively investigate ANAPC1 expression in HCC.Clustered regularly interspaced short palindromic repeats analysis was performed to assess growth in HCC cell lines following ANAPC1 knockout.Enrichment analyses were conducted to explore the functions of ANAPC1.ScRNA-seq data was used to examine the cell cycle and metabolic levels.CellChat analysis was applied to investigate the interactions between ANAPC1 and different cell types.The relationship between ANAPC1 expression and drug concentration was analyzed.RESULTS ANAPC1 messenger RNA was found to be upregulated in bulk RNA,IHC tissues samples and malignant hepatocytes.The proliferation of JHH2 cell lines was most significantly inhibited after ANAPC1 knockdown.In biological pathways,the development of HCC was found to be linked to the regulation of ubiquitin-mediated proteolysis.Additionally,scRNA-seq results indicated that highly expressed ANAPC1 was in the G2/M phase,with increased glycolysis/gluconeogenesis activity.A CellChat analysis showed that ANAPC1 was associated with the regulation of the migration inhibitory factor-(cluster of differentiation 74+C-X-C chemokine receptor type 4)pathway.Higher ANAPC1 expression correlated with stronger effects of sorafenib,dasatinib,ibrutinib,lapatinib,nilotinib and afatinib.CONCLUSION The high expression level of ANAPC1 may regulate the cell cycle and metabolic levels of HCC through the ubiquitination-related pathway,thereby promoting disease progression.
