Mucosal melanoma(MM)is a rare melanoma that affects the mucous membranes of the gastrointestinal,respiratory,and genitourinary tracts[1].In contrast to cutaneous melanoma(CM),MM occurs in body areas without sun exposu...Mucosal melanoma(MM)is a rare melanoma that affects the mucous membranes of the gastrointestinal,respiratory,and genitourinary tracts[1].In contrast to cutaneous melanoma(CM),MM occurs in body areas without sun exposure and is more difficult to detect,often overlooked until nodal or metastatic involvement[2].The molecular profile of MM is distinct,with a lower mutational burden and higher degree of chromosomal aberrations than CM,potentially affecting treatment strategies[3].Patients with MM typically receive the same immunotherapy as patients with CM and are not candidates for BRAF/MEK inhibition,an option for many patients with CM[1].However,standard-of-care therapies and immune checkpoint inhibitors(ICIs)are associated with poor outcomes in patients with MM[4–6].展开更多
Background:Cadonilimab is a humanized immunoglobulin G1 bispecific antibody targeting programmed cell death protein 1(PD-1)and cytotoxic Tlymphocyte-associated antigen 4(CTLA-4).This study aimed to evaluate the safety...Background:Cadonilimab is a humanized immunoglobulin G1 bispecific antibody targeting programmed cell death protein 1(PD-1)and cytotoxic Tlymphocyte-associated antigen 4(CTLA-4).This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy(SBRT)combined with cadonilimab in patients with advanced recurrent or refractory solid tumors.Methods:Patients with advanced solid tumors who progressed after at least two lines of systemic treatment,including immunotherapy,and were eligible for SBRT were enrolled.SBRT was administered to patients with highburden/symptomatic lesions in combination with intravenous cadonilimab(6 mg/kg,once every 2 weeks).The primary endpoint was safety.Results:Sixty-three patients were enrolled from August 28,2022,to September 14,2023(median follow-up:9.1 months).Themedian prior treatment linewas 3.0(range 2.0-4.0).Approximately 46.0%(29/63)of patients had received prior PD-1/PD-L1 therapy,36.5%(23/63)and 12.7%(8/63)of patients had non-small cell lung cancer and soft tissue sarcoma.Treatment-related adverse events(TRAEs)occurred in 38.1%(24/63)of patients,with grade 3 TRAEs reported in 3.2%(2/63).Themost common TRAEs included pain(12.7%),elevated transaminases(12.7%),pneumonia(6.4%),fatigue(6.4%),nausea(4.8%),and fever(4.8%).The objective response rate(ORR)was 23.8%(95%confidence interval[CI],14.0%-36.2%).The median progression-free survival(PFS)was 7.2 months(95%CI,6.3-8.2 months),and the median overall survival(OS)was 10.0 months(95%CI,7.7-12.4 months).The 6-month and 12-month local control rates were 98.4%and 93.0%,respectively.In a subgroup analysis of 23 non-small cell lung cancer patients,the ORR was 17.4%(95%CI,5.0%-38.8%),the median PFS was 6.9 months(95%CI,4.7-9.1 months),and the median OS was 9.1 months(95%CI,7.3-10.9 months).Multivariate analysis indicated that receiving≥6 cycles of cadonilimab and having an Eastern CooperativeOncologyGroup performance status score of 0-1were significantly associated with improved PFS and OS(P<0.05).Conclusions:SBRT in combination with cadonilimab demonstrated manageable toxicity and promising efficacy in heavily pretreated patients with refractory solid tumors.Trial registration:This study was retrospectively registered at ClinicalTrials.gov(NCT05915481)on August 20,2022.展开更多
Dear Editor,The Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)and CRISPR-associated protein 9(Cas9)(CRISPR/Cas9)-mediated generation of somatically genetically engineered mouse models have emerged a...Dear Editor,The Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)and CRISPR-associated protein 9(Cas9)(CRISPR/Cas9)-mediated generation of somatically genetically engineered mouse models have emerged as a new approach for in vivo modeling of cancer[1].Here,we describe a novel DNA-free,easy,rapid,flexible,multiplexable,and robust method to model endometrial neoplasia by CRISPR/Cas9 ribonucleoprotein(RNP)electroporation into the uterus of mice.展开更多
Dear Editor,For patientswith epidermal growth factor receptor(EGFR)mutant non-small cell lung cancer(NSCLC),EGFR tyrosine kinase inhibitors(TKIs)are used as the first-line treatment[1,2].Despite initial therapeutic re...Dear Editor,For patientswith epidermal growth factor receptor(EGFR)mutant non-small cell lung cancer(NSCLC),EGFR tyrosine kinase inhibitors(TKIs)are used as the first-line treatment[1,2].Despite initial therapeutic responses,patients invariably experience disease progression due to acquired drug resistance[3].Resistance arises,in part,because a subset of cancer cells undergoes epithelial-mesenchymal transition(EMT)and remains viable despite exposure to EGFR TKI concentrations that eliminate the bulk population[4].The surviving cells can be re-sensitized to treatment by prolonged culture in the absence of EGFR TKIs,indicating a transient.展开更多
Background:Gastric cancer(GC)is among the most malignant tumors,yet the pathogenesis is not fully understood,especially the lack of detailed information about the mechanisms underlying long non-coding RNA(lncRNA)-medi...Background:Gastric cancer(GC)is among the most malignant tumors,yet the pathogenesis is not fully understood,especially the lack of detailed information about the mechanisms underlying long non-coding RNA(lncRNA)-mediated post-translational modifications.Here,the molecular mechanisms and clinical significance of the novel lncRNA syndecan-binding protein 2-antisense RNA 1(SDCBP2-AS1)in the tumorigenesis and progression of GC were investigated.Methods:The expression levels of SDCBP2-AS1 in 132 pairs of GC and adjacent normal tissues were compared,and the biological functions were assessed in vitro and in vivo.RNA pull-down and immunoprecipitation assays were conducted to clarify the interactions of SDCBP2-AS1 and heterogeneous nuclear ribonucleoprotein(hnRNP)K.RNA-sequencing,immunoprecipitation,immunofluorescence,and luciferase analyses were performed to investigate the functions of SDCBP2-AS1.Results:SDCBP2-AS1 was significantly downregulated in GC tissues and pre-dictive of poor patient prognosis.Silencing of SDCBP2-AS1 promoted the proliferation and migration of GC cells both in vitro and in vivo.Mechanically,SDCBP2-AS1 physically bound to hnRNP K to repress SUMOylation of hnRNP K and facilitated ubiquitination of hnRNP K andβ-catenin,thereby promoting the degradation ofβ-catenin in the cytoplasm.Silencing of SDCBP2-AS1 caused SUMOylation of hnRNP K and stabilizedβ-catenin activity,which altered tran-scription of downstream genes,resulting in tumorigenesis and metastasis of GC.Moreover,the knockdown of hnRNP K partially abrogated the effects of SDCBP2-AS1.Conclusions:SDCBP2-AS1 interacts with hnRNP K to suppress tumorigenesis and metastasis of GC and regulates post-transcriptional modifications of hnRNP K to destabilizeβ-catenin.These findings suggest SDCBP2-AS1 as a potential target for the treatment of GC.展开更多
Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reas...Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.展开更多
Patient-derived cancer cells(PDCs)and patient-derived xenografts(PDXs)are often used as tumor models,but have many shortcomings.PDCs not only lack diversity in terms of cell type,spatial organization,and microenvironm...Patient-derived cancer cells(PDCs)and patient-derived xenografts(PDXs)are often used as tumor models,but have many shortcomings.PDCs not only lack diversity in terms of cell type,spatial organization,and microenvironment but also have adverse effects in stem cell cultures,whereas PDX are expensive with a low transplantation success rate and require a long culture time.In recent years,advances in three-dimensional(3D)organoid culture technology have led to the development of novel physiological systems that model the tissues of origin more precisely than traditional culture methods.Patient-derived cancer organoids bridge the conventional gaps in PDC and PDX models and closely reflect the pathophysiological features of natural tumorigenesis and metastasis,and have led to new patient-specific drug screening techniques,development of individualized treatment regimens,and discovery of prognostic biomarkers and mechanisms of resistance.Synergistic combinations of cancer organoids with other technologies,for example,organ-on-a-chip,3D bio-printing,and CRISPR-Cas9-mediated homology-independent organoid transgenesis,and with treatments, such as immunotherapy, have been useful in overcoming their limitations and led to the development of more suitable model systems that recapitulate the complex stroma of cancer, inter-organ and intra-organ communications,and potentially multiorgan metastasis. In this review, we discuss various methods for the creation of organ-specific cancer organoids and summarize organspecific advances and applications, synergistic technologies, and treatments aswell as current limitations and future prospects for cancer organoids. Furtheradvances will bring this novel 3D organoid culture technique closer to clinicalpractice in the future.展开更多
The standard of care for patients with locoregionally advanced nasopharyngeal carcinoma is concurrent platinum-based chemoradiotherapy.Existing literature have demonstrated that the addition of gemcitabine and cisplat...The standard of care for patients with locoregionally advanced nasopharyngeal carcinoma is concurrent platinum-based chemoradiotherapy.Existing literature have demonstrated that the addition of gemcitabine and cisplatin as induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma may have promising efficacy but were from phase 2 clinical trials.Stronger evidence-based data in forms of phase 3 clinical trial investigating the survival benefits of adding gemcitabine and cisplatin induction chemotherapy for such patients have been urgently warranted.In one of our recent studies published in the New England Journal of Medicine,“Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma”,480 locoregionally advanced nasopharyngeal carcinoma patients from 12 hospitals across China were randomly assigned in a 1:1 ratio to receive either chemoradiotherapy alone or gemcitabine plus cisplatin and chemoradiotherapy.Our findings evinced that,as compared to chemora-diotherapy alone,the addition of induction chemotherapy comprising of gemcitabine plus cisplatin to concurrent cisplatin-radiotherapy to patients with locoregionally advanced nasopharyngeal carcinoma was safe,demonstrated improved recurrence-free survival,overall survival,and distant recurrence-free survival,and marginally superior locore-gional recurrence-free survival.展开更多
A metabolic switch favoring glycolysis over aerobic oxidative phosphorylation,termed the“Warburg effect”,is a hallmark of cancer cells[1].Hexokinase(HK)catalyzes the first and irreversible step of glycolysis,thereby...A metabolic switch favoring glycolysis over aerobic oxidative phosphorylation,termed the“Warburg effect”,is a hallmark of cancer cells[1].Hexokinase(HK)catalyzes the first and irreversible step of glycolysis,thereby limiting overall glycolytic activity.Mammals encode five HK family members:HK1-4 and HKDC1(HK domain containing 1).HKDC1 has an exceptionally low glucose affinity and,therefore,low hexokinase activity under physiological conditions[2],raising questions about its function.A recent study indicated that HKDC1 functions as a glucose sensor within the tumor microenvironment[3],and its dysregulated expression has been associated with chronic inflammation[4]and various cancers[5].展开更多
Prostate cancer is a common cancer among men world-wide.Large-scale clinicalstudies of the 1,000 mg daily dos-ing of abiraterone acetate(AA)have confirmed its antitu-mor efficacy in patients with metastatic hormone-se...Prostate cancer is a common cancer among men world-wide.Large-scale clinicalstudies of the 1,000 mg daily dos-ing of abiraterone acetate(AA)have confirmed its antitu-mor efficacy in patients with metastatic hormone-sensitiveprostate cancer(mHSPC)or metastatic castration-resistantprostate cancer(mCRPC),regardless of their cancer’sresponse to androgen deprivation therapy(ADT)or treat-ment duration.However,this dosage was indirectly jus-tified based on the absence of dose-limiting toxicities(DLTs)in prior phase I dose-escalation trials,where aplateau in the increase of upstream steroids relating tosecondary mineralocorticoid excess was observed at dosesgreater than 750 mg and up to 2,000 mg daily[1,2].Notably,prostate specific antigen(PSA)levels declined atall investigated doses(250 to 1,000 mg)[1,2].展开更多
Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dM...Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dMMR)functions and poor response in patients with proficientMMR(pMMR).pMMRtumors are generally immunogenically“cold”,emphasizing combination strategies to turn the“cold”tumor“hot”to enhance the efficacy of ICIs.ATR inhibitors(ATRi)have been proven to cooperate with radiation to promote antitumor immunity,but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs.This study aimed to investigate the efficacy of combining ATRi,irradiation(IR),and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses.Methods:The efficacy of combining ATRi,IR,and anti-PD-L1 antibodies was evaluated in CRC tumors.The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens.The mechanisms were explored via cell viability assay,flow cytometry,immunofluorescence,immunoblotting,co-immunoprecipitation,and real-time quantitative PCR in multiple murine and human CRC cell lines.Results:Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses.The mechanistic study demonstrated that IR+ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STINGp65 axis,via promoting SUMOylation of SHP1 at lysine 127.By boosting the STING signaling,IR+ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment,thus facilitating immunotherapy.Conclusions:The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses.The new combination strategy raised by our study isworth investigating in the management of CRC.展开更多
Dear Editor,Short-term fasting(up to 48 hours)activates strong physiological and molecular responses[1].We and others showed a p53-independent transcriptional activation of the cell cycle inhibitor p21 upon fasting,mo...Dear Editor,Short-term fasting(up to 48 hours)activates strong physiological and molecular responses[1].We and others showed a p53-independent transcriptional activation of the cell cycle inhibitor p21 upon fasting,most strongly in the liver,muscles,and many other tissues[2,3].Studies with mice[4,5]and human patients[6]have shown the beneficial effects of short-term fasting during anti-cancer chemotherapy treatments.展开更多
Background:Understanding how the tumor microenvironment is shaped by various factors is important for the development of new therapeutic strategies.Tumor cells often undergo spontaneous apoptotic cell death in tumor m...Background:Understanding how the tumor microenvironment is shaped by various factors is important for the development of new therapeutic strategies.Tumor cells often undergo spontaneous apoptotic cell death in tumor microen-vironment,these apoptotic cells are histologically co-localized with immunosup-pressive macrophages.However,the mechanism by which tumor cell apoptosis modulates macrophage polarization is not fully understood.In this study,we aimed to explore the tumor promoting effects of apoptotic tumor cells and the signal pathways involved.Methods:Apoptotic cells and macrophages in tumors were detected by immunohistochemical staining.Morphological analysis was performed with Giemsa staining.Lipids generated from apoptotic cells were detected by liq-uid chromatography-mass spectrometry.Phosphatidylserine-containing lipo-somes were prepared to mimic apoptotic cells.The expression of protein was determined by real-time PCR,immunohistochemistry enzyme-linked immunosorbent assay and Western blotting.Mouse malignant ascites and subcu-taneous tumor models were designed for in vivo analysis.Transgenic mice with specific genes knocked out and inhibitors specific to certain proteins were used for the mechanistic studies.Results:The location and the number of apoptotic cells were correlated with that of macrophages in several types of carcinomas.Phosphatidylserine,a lipid molecule generated in apoptotic cells,induced polarization and accumulation of M2-like macrophages in vivo and in vitro.Moreover,sustained administration of phosphoserine promoted tumor growth in the malignant ascites and subcuta-neous tumor models.Further analyses suggested that phosphoserine induced a M2-like phenotype in macrophages,which was related to the activation of phosphoserine receptors including T-cell immunoglobin mucin 4(TIM4)and the FAK-SRC-STAT3 signaling pathway as well as elevated the expression of the histone demethylase Jumonji domain-containing protein 3(JMJD3).Adminis-tration of specific inhibitors of these pathways could reduce tumor progression.Conclusions:This study suggest that apoptotic cell-generated phosphoserine might be a notable signal for immunosuppressive macrophages in tumors,and the related pathways might be potential therapeutic targets for cancer therapy.展开更多
Dear Editor,Appendectomy is usually performed to treat acute appendicitis although it may also be conducted in the absence of appendicitis when patients suffer from chronic abdominal pain.Resection is also known to mi...Dear Editor,Appendectomy is usually performed to treat acute appendicitis although it may also be conducted in the absence of appendicitis when patients suffer from chronic abdominal pain.Resection is also known to mitigate the risk of ulcerative colitis[1],a risk factor for colorectal cancer.The impact of appendectomy on colorectal cancer risk,particularly in the long term,is unclear.The procedurewas initially hypothesized to increase colorectal cancer risk due to decreased immunocompetency.展开更多
Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and im...Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.展开更多
Background:Lynch syndrome(LS)is a hereditary condition characterized by a high risk of colorectal cancer,endometrial cancer,and other neoplasia associated with germline alterations in DNA mismatch repair genes.The cla...Background:Lynch syndrome(LS)is a hereditary condition characterized by a high risk of colorectal cancer,endometrial cancer,and other neoplasia associated with germline alterations in DNA mismatch repair genes.The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome.Next-generation sequencing(NGS)enables the simultaneous sequencing of a large number of hereditary cancer genes.Here,we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.Methods:A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture.The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants.The findings of NGS were confirmed by Sanger sequencing.When possible,genetic analyses of the new findings in the proband’s relativeswere also performed by Sanger sequencing.Results:We identified five families(6%),out of 84,with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes:[MLH1-BRCA2-NBN],[MLH1-BRCA1],[MSH2-ATM],[MSH6-NF1],and[MLH1-FANCA].Interestingly,only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants.The family with three pathogenic variants of the[MLH1-BRCA2-NBN]genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.Conclusions:Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS.Inmost cases,no clinicial manifestations were associated with the secondary pathogenic variants.Further studies are needed to confirm these findings and elucidate their clinical impact.Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.展开更多
Background:Evading immune surveillance is necessary for tumor metastasis.Thus,there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion.In this study,we aim...Background:Evading immune surveillance is necessary for tumor metastasis.Thus,there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion.In this study,we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma(ESCC).Methods:The expression of melanoma-associated antigen C3(MAGE-C3)was detected using immunohistochemistry.Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma(ESCC)cells.Metastasis assays in mice were used to evaluate metastatic ability in vivo.Lymphocyte-mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells.RNA sequencing was performed to identify differentially expressed genes between MAGE-C3 overexpressing ESCC cells and control cells.Gene ontology(GO)enrichment analyses was performed to identify the most altered pathways influenced by MAGE-C3.The activation of the interferon-γ(IFN-γ)pathway was analyzed using Western blotting,GAS luciferase reporter assays,immunofluorescence,and flow cytometry.The role of MAGE-C3 in the IFN-γpathway was determined by Western blotting and immunoprecipitation.Furthermore,immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.Results:MAGE-C3 was overexpressed in ESCC tissues.High expression of MAGE-C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC.Functional experiments revealed that MAGE-C3 promoted tumor metastasis by activating the epithelial-mesenchymal transition(EMT).MAGE-C3 repressed antitumor immunity and regulated cytokine secretion of T cells,implying an immunosuppressive function.Mechanistically,MAGE-C3 facilitated IFN-γsignaling and upregulated programmed cell death ligand 1(PDŋL1)by binding with IFN-γreceptor 1(IFNGR1)and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1(STAT1).Interestingly,MAGE-C3 displayed higher tumorigenesis in immune-competent mice than in immune-deficient nude mice,confirming the immunosuppressive role of MAGE-C3.Furthermore,mice bearing MAGE-C3-overexpressing tumors showed worse survival and more lung metastases with decreased CD8+infiltrated T cells and increased programmed cell death 1(PD-1)^(+)CD8^(+) infiltrated T cells.Conclusion:MAGE-C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance,and could be a potential prognostic marker and therapeutic target.展开更多
The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important rol...The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important roles in a variety of cellular processes implicated in tumorigenesis,including cell cycle,cell proliferation,apoptosis,metastasis,mitophagy and metabolic reprogramming.Here we review the role and mechanism of Parkin in cancer.展开更多
Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate th...Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC.Methods:In this real-world study(ChiCTR2000030266),patientswith advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1,2018 and December 31,2019 were retrospectively analyzed.Interpretation training was conducted before the study was initiated.Quality controls were performed at participating centers using immunohistochemistry(IHC)-VENTANA-D5F3.The positive ALK gene rearrangement rate and consistency rate were calculated.The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well.Results:The overall ALK gene rearrangement rate was 6.7%in 23,689 patients with advanced NSCLC and 8.2%in 17,436 patients with advanced lung adenocarcinoma.The quality control analysis of IHC-VENTANA-D5F3 revealed an intrahospital consistency rate of 98.2%(879/895)and an inter-hospital consistency rate of 99.2%(646/651).IHC-VENTANA-D5F3 was used in 53.6%,real-time polymerase chain reaction(RT-PCR)in 25.4%,next-generation sequencing(NGS)in 18.3%,and fluorescence in-situ hybridization(FISH)in 15.9%in the adenocarcinoma subgroup.For specimens tested with multiple methods,the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0%(822/839)for FISH,98.7%(1,222/1,238)forNGS,and 91.3%(146/160)for RT-PCR.The overall ALK gene rearrangement rateswere higher in females,patients of≤35 years old,never smokers,tumor cellularity of>50,and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup(all P<0.05).Conclusions:This study highlights the real-world variability and challenges of ALK test in advanced NSCLC,demonstrating a predominant use of IHCVENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients.These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.展开更多
Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor ...Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].展开更多
基金This study was sponsored by Iovance Biotherapeutics,Inc.(San Carlos,CA,USA).
文摘Mucosal melanoma(MM)is a rare melanoma that affects the mucous membranes of the gastrointestinal,respiratory,and genitourinary tracts[1].In contrast to cutaneous melanoma(CM),MM occurs in body areas without sun exposure and is more difficult to detect,often overlooked until nodal or metastatic involvement[2].The molecular profile of MM is distinct,with a lower mutational burden and higher degree of chromosomal aberrations than CM,potentially affecting treatment strategies[3].Patients with MM typically receive the same immunotherapy as patients with CM and are not candidates for BRAF/MEK inhibition,an option for many patients with CM[1].However,standard-of-care therapies and immune checkpoint inhibitors(ICIs)are associated with poor outcomes in patients with MM[4–6].
基金Ministry of Education,China University Industry-University-Research Innovation Fund,Grant/Award Number:2023HT009。
文摘Background:Cadonilimab is a humanized immunoglobulin G1 bispecific antibody targeting programmed cell death protein 1(PD-1)and cytotoxic Tlymphocyte-associated antigen 4(CTLA-4).This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy(SBRT)combined with cadonilimab in patients with advanced recurrent or refractory solid tumors.Methods:Patients with advanced solid tumors who progressed after at least two lines of systemic treatment,including immunotherapy,and were eligible for SBRT were enrolled.SBRT was administered to patients with highburden/symptomatic lesions in combination with intravenous cadonilimab(6 mg/kg,once every 2 weeks).The primary endpoint was safety.Results:Sixty-three patients were enrolled from August 28,2022,to September 14,2023(median follow-up:9.1 months).Themedian prior treatment linewas 3.0(range 2.0-4.0).Approximately 46.0%(29/63)of patients had received prior PD-1/PD-L1 therapy,36.5%(23/63)and 12.7%(8/63)of patients had non-small cell lung cancer and soft tissue sarcoma.Treatment-related adverse events(TRAEs)occurred in 38.1%(24/63)of patients,with grade 3 TRAEs reported in 3.2%(2/63).Themost common TRAEs included pain(12.7%),elevated transaminases(12.7%),pneumonia(6.4%),fatigue(6.4%),nausea(4.8%),and fever(4.8%).The objective response rate(ORR)was 23.8%(95%confidence interval[CI],14.0%-36.2%).The median progression-free survival(PFS)was 7.2 months(95%CI,6.3-8.2 months),and the median overall survival(OS)was 10.0 months(95%CI,7.7-12.4 months).The 6-month and 12-month local control rates were 98.4%and 93.0%,respectively.In a subgroup analysis of 23 non-small cell lung cancer patients,the ORR was 17.4%(95%CI,5.0%-38.8%),the median PFS was 6.9 months(95%CI,4.7-9.1 months),and the median OS was 9.1 months(95%CI,7.3-10.9 months).Multivariate analysis indicated that receiving≥6 cycles of cadonilimab and having an Eastern CooperativeOncologyGroup performance status score of 0-1were significantly associated with improved PFS and OS(P<0.05).Conclusions:SBRT in combination with cadonilimab demonstrated manageable toxicity and promising efficacy in heavily pretreated patients with refractory solid tumors.Trial registration:This study was retrospectively registered at ClinicalTrials.gov(NCT05915481)on August 20,2022.
基金supported by the Spanish Ministry of Science,Innovation and Universities(grant code PID2019-104734RB-I00)and the Spanish Association Against Cancer(grant code LABAE19004LLOB).This work was also funded by the Institute of Health Carlos III(MS17/00063)(co-founded by the European Social Fund[ESF]“investing in your future”).
文摘Dear Editor,The Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)and CRISPR-associated protein 9(Cas9)(CRISPR/Cas9)-mediated generation of somatically genetically engineered mouse models have emerged as a new approach for in vivo modeling of cancer[1].Here,we describe a novel DNA-free,easy,rapid,flexible,multiplexable,and robust method to model endometrial neoplasia by CRISPR/Cas9 ribonucleoprotein(RNP)electroporation into the uterus of mice.
基金the Roswell Park Alliance Foundation(Taste of Life Award),the American Lung Association Lung Cancer Discovery Award LCD615335,S10OD010393-01the Roswell Park Cancer Center Support Grant P30 CA016056 that supports the Laboratory Animal Shared Resource and Translational Imaging Shared Resource utilized in this work.
文摘Dear Editor,For patientswith epidermal growth factor receptor(EGFR)mutant non-small cell lung cancer(NSCLC),EGFR tyrosine kinase inhibitors(TKIs)are used as the first-line treatment[1,2].Despite initial therapeutic responses,patients invariably experience disease progression due to acquired drug resistance[3].Resistance arises,in part,because a subset of cancer cells undergoes epithelial-mesenchymal transition(EMT)and remains viable despite exposure to EGFR TKI concentrations that eliminate the bulk population[4].The surviving cells can be re-sensitized to treatment by prolonged culture in the absence of EGFR TKIs,indicating a transient.
基金the National High Technology Research and Development Program of China,Grant/Award Number:2014AA020603Clinical Medicine Plus X-Young Scholars Project of Peking University,Grant/Award Number:PKU2020LCXQ001+4 种基金the Joint Fund for the Key Projects of National Natural Science Foundation of China,Grant/Award Number:U20A20371“Double First Class”disciplinary development Foundation of Peking University,Grant/Award Number:BMU2019LCKXJ011National Natural Science Foundation of China,Grant/Award Numbers:81802471,81872502,81972758,82103528Beijing Municipal Medical Research Institutes,Grant/Award Number:2019-1Beijing municipal administration of hospitals’youth program,Grant/Award Number:QML20181102。
文摘Background:Gastric cancer(GC)is among the most malignant tumors,yet the pathogenesis is not fully understood,especially the lack of detailed information about the mechanisms underlying long non-coding RNA(lncRNA)-mediated post-translational modifications.Here,the molecular mechanisms and clinical significance of the novel lncRNA syndecan-binding protein 2-antisense RNA 1(SDCBP2-AS1)in the tumorigenesis and progression of GC were investigated.Methods:The expression levels of SDCBP2-AS1 in 132 pairs of GC and adjacent normal tissues were compared,and the biological functions were assessed in vitro and in vivo.RNA pull-down and immunoprecipitation assays were conducted to clarify the interactions of SDCBP2-AS1 and heterogeneous nuclear ribonucleoprotein(hnRNP)K.RNA-sequencing,immunoprecipitation,immunofluorescence,and luciferase analyses were performed to investigate the functions of SDCBP2-AS1.Results:SDCBP2-AS1 was significantly downregulated in GC tissues and pre-dictive of poor patient prognosis.Silencing of SDCBP2-AS1 promoted the proliferation and migration of GC cells both in vitro and in vivo.Mechanically,SDCBP2-AS1 physically bound to hnRNP K to repress SUMOylation of hnRNP K and facilitated ubiquitination of hnRNP K andβ-catenin,thereby promoting the degradation ofβ-catenin in the cytoplasm.Silencing of SDCBP2-AS1 caused SUMOylation of hnRNP K and stabilizedβ-catenin activity,which altered tran-scription of downstream genes,resulting in tumorigenesis and metastasis of GC.Moreover,the knockdown of hnRNP K partially abrogated the effects of SDCBP2-AS1.Conclusions:SDCBP2-AS1 interacts with hnRNP K to suppress tumorigenesis and metastasis of GC and regulates post-transcriptional modifications of hnRNP K to destabilizeβ-catenin.These findings suggest SDCBP2-AS1 as a potential target for the treatment of GC.
基金Science Fund for Creative Research Groups of the National Natural Science Foundation of China,Grant/Award Number:81521004National Natural Science Foundation of China,Grant/Award Numbers:81922061,82172992,81903391,81702266+2 种基金Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers,Chinese Academy of Medical Sciences,Grant/Award Number:2019RU038Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211253,BK20190148Postgraduate Research&Practice Innovation Program of Jiangsu Province,Grant/Award Number:KYCX18_0195。
文摘Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.
基金supported by the National Natural Science Foundation of China(81802278 and 81900563)the Natural Science Foundation of Hunan Province(2019JJ50361 and 2020JJ4418).
文摘Patient-derived cancer cells(PDCs)and patient-derived xenografts(PDXs)are often used as tumor models,but have many shortcomings.PDCs not only lack diversity in terms of cell type,spatial organization,and microenvironment but also have adverse effects in stem cell cultures,whereas PDX are expensive with a low transplantation success rate and require a long culture time.In recent years,advances in three-dimensional(3D)organoid culture technology have led to the development of novel physiological systems that model the tissues of origin more precisely than traditional culture methods.Patient-derived cancer organoids bridge the conventional gaps in PDC and PDX models and closely reflect the pathophysiological features of natural tumorigenesis and metastasis,and have led to new patient-specific drug screening techniques,development of individualized treatment regimens,and discovery of prognostic biomarkers and mechanisms of resistance.Synergistic combinations of cancer organoids with other technologies,for example,organ-on-a-chip,3D bio-printing,and CRISPR-Cas9-mediated homology-independent organoid transgenesis,and with treatments, such as immunotherapy, have been useful in overcoming their limitations and led to the development of more suitable model systems that recapitulate the complex stroma of cancer, inter-organ and intra-organ communications,and potentially multiorgan metastasis. In this review, we discuss various methods for the creation of organ-specific cancer organoids and summarize organspecific advances and applications, synergistic technologies, and treatments aswell as current limitations and future prospects for cancer organoids. Furtheradvances will bring this novel 3D organoid culture technique closer to clinicalpractice in the future.
文摘The standard of care for patients with locoregionally advanced nasopharyngeal carcinoma is concurrent platinum-based chemoradiotherapy.Existing literature have demonstrated that the addition of gemcitabine and cisplatin as induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma may have promising efficacy but were from phase 2 clinical trials.Stronger evidence-based data in forms of phase 3 clinical trial investigating the survival benefits of adding gemcitabine and cisplatin induction chemotherapy for such patients have been urgently warranted.In one of our recent studies published in the New England Journal of Medicine,“Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma”,480 locoregionally advanced nasopharyngeal carcinoma patients from 12 hospitals across China were randomly assigned in a 1:1 ratio to receive either chemoradiotherapy alone or gemcitabine plus cisplatin and chemoradiotherapy.Our findings evinced that,as compared to chemora-diotherapy alone,the addition of induction chemotherapy comprising of gemcitabine plus cisplatin to concurrent cisplatin-radiotherapy to patients with locoregionally advanced nasopharyngeal carcinoma was safe,demonstrated improved recurrence-free survival,overall survival,and distant recurrence-free survival,and marginally superior locore-gional recurrence-free survival.
基金supported by the German Research Foundation(DFG)through the individual grant SO1141/10-1,the Research Unit FOR5042“miTarget-The Microbiome as a Target in Inflammatory Bowel Diseases”(project P5)the Excellence Cluster EXS2167“Precision Medicine in Chronic Inflammation”,an intramural grant of the medical faculty of Kiel University(grant no K126408)Felix Sommer and ZMB Young Scientist Award 2021,category doctoral students(grant no F384430)to Lea Järke.
文摘A metabolic switch favoring glycolysis over aerobic oxidative phosphorylation,termed the“Warburg effect”,is a hallmark of cancer cells[1].Hexokinase(HK)catalyzes the first and irreversible step of glycolysis,thereby limiting overall glycolytic activity.Mammals encode five HK family members:HK1-4 and HKDC1(HK domain containing 1).HKDC1 has an exceptionally low glucose affinity and,therefore,low hexokinase activity under physiological conditions[2],raising questions about its function.A recent study indicated that HKDC1 functions as a glucose sensor within the tumor microenvironment[3],and its dysregulated expression has been associated with chronic inflammation[4]and various cancers[5].
基金funded by Joseph Lim Boon Tiong UrologyCancer Research(Grant:A-0002678-01-00).
文摘Prostate cancer is a common cancer among men world-wide.Large-scale clinicalstudies of the 1,000 mg daily dos-ing of abiraterone acetate(AA)have confirmed its antitu-mor efficacy in patients with metastatic hormone-sensitiveprostate cancer(mHSPC)or metastatic castration-resistantprostate cancer(mCRPC),regardless of their cancer’sresponse to androgen deprivation therapy(ADT)or treat-ment duration.However,this dosage was indirectly jus-tified based on the absence of dose-limiting toxicities(DLTs)in prior phase I dose-escalation trials,where aplateau in the increase of upstream steroids relating tosecondary mineralocorticoid excess was observed at dosesgreater than 750 mg and up to 2,000 mg daily[1,2].Notably,prostate specific antigen(PSA)levels declined atall investigated doses(250 to 1,000 mg)[1,2].
基金Innovative Capacity Building Project of the Hubei Engineering Research Center for Radiotherapy and Radiation Protection of Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Grant/Award Number:2018-420114-35-03-071705State Key Program of National Natural Science of China,Grant/Award Number:82130092National Natural Science Foundation of China,Grant/Award Numbers:81372664,81902619。
文摘Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dMMR)functions and poor response in patients with proficientMMR(pMMR).pMMRtumors are generally immunogenically“cold”,emphasizing combination strategies to turn the“cold”tumor“hot”to enhance the efficacy of ICIs.ATR inhibitors(ATRi)have been proven to cooperate with radiation to promote antitumor immunity,but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs.This study aimed to investigate the efficacy of combining ATRi,irradiation(IR),and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses.Methods:The efficacy of combining ATRi,IR,and anti-PD-L1 antibodies was evaluated in CRC tumors.The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens.The mechanisms were explored via cell viability assay,flow cytometry,immunofluorescence,immunoblotting,co-immunoprecipitation,and real-time quantitative PCR in multiple murine and human CRC cell lines.Results:Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses.The mechanistic study demonstrated that IR+ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STINGp65 axis,via promoting SUMOylation of SHP1 at lysine 127.By boosting the STING signaling,IR+ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment,thus facilitating immunotherapy.Conclusions:The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses.The new combination strategy raised by our study isworth investigating in the management of CRC.
基金the Spanish association against cancer(AECC)(id:SIRTBIO-LABAE18008FERN and PRDMA18011PAST)Pablo J.Fernandez-Marcos has been funded by a Ramon y Cajal Award from the Spanish Ministry of Science,Innovation and Universities(MICINN)(RYC-2017-22335)+2 种基金Marta Barradas and Cristina Pantoja have been funded by Madrid Institute for Advanced Studies(IMDEA)Food.Jose L.López-Aceituno has been funded by the Spanish Ministry of Science and Innovation(MICINN)(PTA2017-14689-I)Work at the laboratory of Pablo J.Fernandez-Marcos was funded by the AECC(SIRTBIO-LABAE18008FERN)the RETOS projects Programme of MICINN(SAF2017-85766-R and PID2020-114077RB-I00).
文摘Dear Editor,Short-term fasting(up to 48 hours)activates strong physiological and molecular responses[1].We and others showed a p53-independent transcriptional activation of the cell cycle inhibitor p21 upon fasting,most strongly in the liver,muscles,and many other tissues[2,3].Studies with mice[4,5]and human patients[6]have shown the beneficial effects of short-term fasting during anti-cancer chemotherapy treatments.
基金NationalNatural Science Foundation of China:National Science Foundation for ExcellentYoung Scholars,Grant/Award Number:32122052NationalNatural Sci-ence Foundation of China:NationalNat-ural Science FoundationRegional Inno-vation and Development,Grant/Award Number:U19A2003NationalNatural Science Foundation ofChina:National Science Foundation forYoung Scholars,Grant/Award Number:81902662。
文摘Background:Understanding how the tumor microenvironment is shaped by various factors is important for the development of new therapeutic strategies.Tumor cells often undergo spontaneous apoptotic cell death in tumor microen-vironment,these apoptotic cells are histologically co-localized with immunosup-pressive macrophages.However,the mechanism by which tumor cell apoptosis modulates macrophage polarization is not fully understood.In this study,we aimed to explore the tumor promoting effects of apoptotic tumor cells and the signal pathways involved.Methods:Apoptotic cells and macrophages in tumors were detected by immunohistochemical staining.Morphological analysis was performed with Giemsa staining.Lipids generated from apoptotic cells were detected by liq-uid chromatography-mass spectrometry.Phosphatidylserine-containing lipo-somes were prepared to mimic apoptotic cells.The expression of protein was determined by real-time PCR,immunohistochemistry enzyme-linked immunosorbent assay and Western blotting.Mouse malignant ascites and subcu-taneous tumor models were designed for in vivo analysis.Transgenic mice with specific genes knocked out and inhibitors specific to certain proteins were used for the mechanistic studies.Results:The location and the number of apoptotic cells were correlated with that of macrophages in several types of carcinomas.Phosphatidylserine,a lipid molecule generated in apoptotic cells,induced polarization and accumulation of M2-like macrophages in vivo and in vitro.Moreover,sustained administration of phosphoserine promoted tumor growth in the malignant ascites and subcuta-neous tumor models.Further analyses suggested that phosphoserine induced a M2-like phenotype in macrophages,which was related to the activation of phosphoserine receptors including T-cell immunoglobin mucin 4(TIM4)and the FAK-SRC-STAT3 signaling pathway as well as elevated the expression of the histone demethylase Jumonji domain-containing protein 3(JMJD3).Adminis-tration of specific inhibitors of these pathways could reduce tumor progression.Conclusions:This study suggest that apoptotic cell-generated phosphoserine might be a notable signal for immunosuppressive macrophages in tumors,and the related pathways might be potential therapeutic targets for cancer therapy.
基金The French E3N cohort is maintained with the support of the Mutuelle Générale de l’Education Nationale(MGEN),Gustave Roussy and the French League against Cancer(LNCC).E3N-E4N is also supported by the French National Research Agency(ANR)under the Investment for the future Program(PIA)(ANR-10-COHO-0006)by the French Ministry of Higher Education,Research and Innovation(subsidy#2102918823).
文摘Dear Editor,Appendectomy is usually performed to treat acute appendicitis although it may also be conducted in the absence of appendicitis when patients suffer from chronic abdominal pain.Resection is also known to mitigate the risk of ulcerative colitis[1],a risk factor for colorectal cancer.The impact of appendectomy on colorectal cancer risk,particularly in the long term,is unclear.The procedurewas initially hypothesized to increase colorectal cancer risk due to decreased immunocompetency.
基金National Key Research and Development Plan,Grant/Award Number:2017YFA0506000Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021B1515120016+1 种基金National Natural Science Foundation of China,Grant/Award Number:82072822the Key Research and Development Program of Jiangsu Province,China-Social Development Projects,Grant/Award Number:BE2020687。
文摘Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.
基金supported by grants from the Foundation for the Promotion of Health and Biomedical Research in the Valencian Region,FISABIO(Grants:UGP-14-192 and UGP-16-146)the Carlos Ⅲ Health Institute(Grant AES:PI17/01082).
文摘Background:Lynch syndrome(LS)is a hereditary condition characterized by a high risk of colorectal cancer,endometrial cancer,and other neoplasia associated with germline alterations in DNA mismatch repair genes.The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome.Next-generation sequencing(NGS)enables the simultaneous sequencing of a large number of hereditary cancer genes.Here,we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.Methods:A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture.The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants.The findings of NGS were confirmed by Sanger sequencing.When possible,genetic analyses of the new findings in the proband’s relativeswere also performed by Sanger sequencing.Results:We identified five families(6%),out of 84,with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes:[MLH1-BRCA2-NBN],[MLH1-BRCA1],[MSH2-ATM],[MSH6-NF1],and[MLH1-FANCA].Interestingly,only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants.The family with three pathogenic variants of the[MLH1-BRCA2-NBN]genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.Conclusions:Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS.Inmost cases,no clinicial manifestations were associated with the secondary pathogenic variants.Further studies are needed to confirm these findings and elucidate their clinical impact.Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.
基金This study was supported by grants from the National Natural Science Foundation of China(81988101,81830086,82003007 and 81802780)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Funding by Major Program of Shenzhen Bay Laboratory(S201101004)Project funded by China Postdoctoral Science Foundation(2019M6603068)Science Foundation of Peking University Cancer Hospital(2020-16).
文摘Background:Evading immune surveillance is necessary for tumor metastasis.Thus,there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion.In this study,we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma(ESCC).Methods:The expression of melanoma-associated antigen C3(MAGE-C3)was detected using immunohistochemistry.Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma(ESCC)cells.Metastasis assays in mice were used to evaluate metastatic ability in vivo.Lymphocyte-mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells.RNA sequencing was performed to identify differentially expressed genes between MAGE-C3 overexpressing ESCC cells and control cells.Gene ontology(GO)enrichment analyses was performed to identify the most altered pathways influenced by MAGE-C3.The activation of the interferon-γ(IFN-γ)pathway was analyzed using Western blotting,GAS luciferase reporter assays,immunofluorescence,and flow cytometry.The role of MAGE-C3 in the IFN-γpathway was determined by Western blotting and immunoprecipitation.Furthermore,immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.Results:MAGE-C3 was overexpressed in ESCC tissues.High expression of MAGE-C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC.Functional experiments revealed that MAGE-C3 promoted tumor metastasis by activating the epithelial-mesenchymal transition(EMT).MAGE-C3 repressed antitumor immunity and regulated cytokine secretion of T cells,implying an immunosuppressive function.Mechanistically,MAGE-C3 facilitated IFN-γsignaling and upregulated programmed cell death ligand 1(PDŋL1)by binding with IFN-γreceptor 1(IFNGR1)and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1(STAT1).Interestingly,MAGE-C3 displayed higher tumorigenesis in immune-competent mice than in immune-deficient nude mice,confirming the immunosuppressive role of MAGE-C3.Furthermore,mice bearing MAGE-C3-overexpressing tumors showed worse survival and more lung metastases with decreased CD8+infiltrated T cells and increased programmed cell death 1(PD-1)^(+)CD8^(+) infiltrated T cells.Conclusion:MAGE-C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance,and could be a potential prognostic marker and therapeutic target.
基金supported by grants to Z.F.from the NIH(R01CA227912)Rutgers Cancer Institute of New Jersey Pilot Award,and by grants to W.H.from the NIH(R01CA160558,R01CA203965)Ellison Medical Foundation.
文摘The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important roles in a variety of cellular processes implicated in tumorigenesis,including cell cycle,cell proliferation,apoptosis,metastasis,mitophagy and metabolic reprogramming.Here we review the role and mechanism of Parkin in cancer.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2021-1-I2M-012,2022-I2M-C&T-B-078Beijing Hope Run Special Fund of Cancer Foundation of the People’s Republic of China,Grant/Award Number:LC2019L04+1 种基金National Key Research and Development Program,Grant/Award Number:2022YFC2409902Capital’s Funds for Health Improvement and Research,Grant/Award Number:2020-2Z-4028。
文摘Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC.Methods:In this real-world study(ChiCTR2000030266),patientswith advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1,2018 and December 31,2019 were retrospectively analyzed.Interpretation training was conducted before the study was initiated.Quality controls were performed at participating centers using immunohistochemistry(IHC)-VENTANA-D5F3.The positive ALK gene rearrangement rate and consistency rate were calculated.The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well.Results:The overall ALK gene rearrangement rate was 6.7%in 23,689 patients with advanced NSCLC and 8.2%in 17,436 patients with advanced lung adenocarcinoma.The quality control analysis of IHC-VENTANA-D5F3 revealed an intrahospital consistency rate of 98.2%(879/895)and an inter-hospital consistency rate of 99.2%(646/651).IHC-VENTANA-D5F3 was used in 53.6%,real-time polymerase chain reaction(RT-PCR)in 25.4%,next-generation sequencing(NGS)in 18.3%,and fluorescence in-situ hybridization(FISH)in 15.9%in the adenocarcinoma subgroup.For specimens tested with multiple methods,the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0%(822/839)for FISH,98.7%(1,222/1,238)forNGS,and 91.3%(146/160)for RT-PCR.The overall ALK gene rearrangement rateswere higher in females,patients of≤35 years old,never smokers,tumor cellularity of>50,and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup(all P<0.05).Conclusions:This study highlights the real-world variability and challenges of ALK test in advanced NSCLC,demonstrating a predominant use of IHCVENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients.These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.
文摘Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].
