Background:Published clinical trials have yielded controversial findings regarding the effects of sex on the benefits of immune checkpoint inhibitors(ICIs).Sex-associated differences in the efficacy of immunotherapy r...Background:Published clinical trials have yielded controversial findings regarding the effects of sex on the benefits of immune checkpoint inhibitors(ICIs).Sex-associated differences in the efficacy of immunotherapy remain an important,unresolved question.Methods:We investigated sex-biased molecular profiles across a multitude of biomarkers linked to immunotherapy responses.Multiomics data from major solid tumors in The Cancer Genome Atlas,with sufficient sample sizes(≥50 patients of each sex),were analyzed.Ninety-five molecular markers characterizing 4 distinct aspects of the tumor immune system were summarized and compared.The inverse probability of weights algorithm was used to generate well-balanced sex subgroups.Results:Our results showed that lung squamous cell carcinoma(LUSC),pancreatic adenocarcinoma,and liver hepatocellular carcinoma were the top 3 cancer types with extensive sex-biased biomarker profiles(31/95,15/95,and 14/95,respectively).Notably,although both were categorized as non–small cell lung carcinoma,LUSC harbored significantly more sex-biased immunological features than those of lung adenocarcinoma(p<0.01).We further explored the validity of this finding by analyzing ICI-responsive signatures and individual patient-level data for non–small cell lung carcinoma and found that sex had significant interaction effects on immunotherapy outcomes in LUSC(p_(interaction)<0.05),with women tending to derive greater benefits from ICIs than men.However,this difference was not apparent in the lung adenocarcinoma group(p_(interaction)=0.66),with men and women deriving comparable benefits.Conclusions:We systematically characterized sex-biased profiles of key molecular biomarkers predicting immunotherapy responses across solid tumors,which could pave the way for individualized therapeutic approaches for men and women.展开更多
Lung cancer remains the leading cause of cancer death in 2024,with∼80%being non-small cell lung cancer(NSCLC).Anaplastic lymphoma kinase(ALK)rearrangements occur in∼5%of NSCLC cases,typically treated with ALK inhibi...Lung cancer remains the leading cause of cancer death in 2024,with∼80%being non-small cell lung cancer(NSCLC).Anaplastic lymphoma kinase(ALK)rearrangements occur in∼5%of NSCLC cases,typically treated with ALK inhibitors,though resistance often develops[1].Immunotherapy has been explored for advanced or resistant ALK-positive NSCLC,but immune checkpoint blockade(ICB)treatments have shown limited clinical benefits[1].展开更多
Aim:This study aimed to develop an m6A-related gene signature for predicting the prognosis of clear cell renal cell carcinoma(ccRCC)patients and explore its value in predicting the immunotherapy response.Methods:In to...Aim:This study aimed to develop an m6A-related gene signature for predicting the prognosis of clear cell renal cell carcinoma(ccRCC)patients and explore its value in predicting the immunotherapy response.Methods:In total,530 ccRCC patients with gene expression data in the TCGA cohort were included and classified into the training(n=371)and validation(n=159)sets.Differential expression analyses of 23 m6A regulators between survivors and non-survivors were performed.Subsequently,an m6A-related gene signature was developed via LASSO Cox regression.All patients were categorized into two groups of m6A subtypes,i.e.,low or high m6A score group.The Kaplan-Meier survival curves and Tumor Immune Dysfunction and Exclusion(TIDE)scores of the two m6A subtype groups were compared to measure the gene signature’s predictive value in prognosis and potential immunotherapy response,respectively.Results:Eighteen m6A regulators were significantly differentially expressed between the survivors and non-survivors,and were also related to overall survival(OS).A gene signature containing five selected m6A methylation regulators(KIAA1429,METTL14,IGF2BP2,IGF2BP3,and SRSF2)was developed and showed favorable discrimination in the training(C-index 0.708)and validation(C-index 0.689)sets.Patients with low m6A scores had significantly better OS and lower TIDE scores than those with high m6A scores.Moreover,a robust MRI-based radiomic signature was developed to noninvasively predict the m6A subtype for each patient.Conclusion:We demonstrated the prognostic value of five m6A regulators and constructed a gene signature for prognosis and immunotherapy response prediction among ccRCC patients.In addition,a radiomic signature was developed for noninvasive prediction of the m6A subtype.These findings may promote precision medicine and provide novel insights into the regulation of tumor immune microenvironment.展开更多
Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking ...Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking tumors5 immune evasion will re-activate the host immune systems to eliminate tumors.Immune-checkpoint therapy(ICT)which applies anti-PD-l/PD-Ll or anti-CTLA4 treatment has been a remarkable success in the past few years.However,〜70%of patients cannot gain any clinical benefits from ICT treatment due to the tumorimmunity system's complexity・In the past,germline pathogenic variants have been thought to have only minorheritable contributions to cancer.Results:Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system.The functional components of the immune system are encoded by the host genome,thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response.Indeed,recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by(i)shaping tumor somatic mutations,altering methylation patterns and antigen-presentation capacity or(ii)influencing NK cell's function to modulate lymphocyte infiltration in the tumor microenvironment.In addition,the HLA(types A,B or C)genotypes also shape the landscape of tumor somatic mutations.Conclusion:These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.展开更多
Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based mar...Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.展开更多
Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis.The role of olfactory signaling pathway-related genes(OSPRGs)in glioma has not been fully elucidated.In this study,we ai...Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis.The role of olfactory signaling pathway-related genes(OSPRGs)in glioma has not been fully elucidated.In this study,we aimed to investigate the role and relationship between OSPRGs and glioma.Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts,and the target gene(G Protein Subunit Alpha L,GNAL)was screened.The association of GNAL expression with clinicopathological characteristics,gene mutation landscape,tumor immune microenvironment(TIME),deoxyribonucleic acid(DNA)methylation,and naris-occlusion controlled genes(NOCGs)was performed.Immunohistochemistry was used to evaluate GNAL level in glioma.Further analysis was conducted to evaluate the drug sensitivity,immunotherapy response,and functional enrichment of GNAL.GNAL was an independent prognostic factor,and patients with low GNAL expression have a poor prognosis.Expression of GNAL was closely associated with clinicopathological characteristics,DNA methylation,and several immune-related pathways.Immune infiltration analysis indicated that GNAL levels were negatively correlated with immune scores.GNAL low-expression group showed efficacy with anti-PD-1 therapy.Ten compounds with significantly different half-maximal inhibitory concentration(IC50)values between the GNAL high and low-expression groups were identified.Furthermore,its expression was associated with several immune cells,immune-related genes,and NOCGs.The expression of GNAL is closely associated with clinicopathological characteristics,TIME,and the response to therapeutic interventions,highlighting its potential as a prognostic biomarker for glioma.展开更多
Introduction:Benign lymph nodes have been considered the hubs of immune surveillance in cancer patients.The microenvironment of these lymphoid tissues can be immune suppressed,hence allowing for tumor progression.Unde...Introduction:Benign lymph nodes have been considered the hubs of immune surveillance in cancer patients.The microenvironment of these lymphoid tissues can be immune suppressed,hence allowing for tumor progression.Understanding the spectrum of benign findings in bystander lymph nodes in immune checkpoint blockade therapy could prove to be key to understanding the mechanism and assessing treatment response.Methods:Benign lymph nodes and spleen were evaluated from patients treated with immunotherapy who subsequently received postmortem examination.We used quantitative immunofluorescence(QIF)to assess tumor infiltrating lymphocytes(TIL)and macrophage marker expression and characterized activation status using a novelmultiplexed QIF assay including CD3,GranzymeB,and Ki67.We performedimmunohistochemistry to correlate results of QIF.Results:Benign lymph nodes from non-responders to immunotherapy showed significantly higher expression of cytotoxic markers and proliferation index(Ki67)in T cells compared to responders.Higher expression of PD-L1 in macrophages was also observed.There was no significant difference in CD3+expression,but higher levels of CD8+T cells as well as CD20+B cells were seen in lymph nodes of non-responders.No significant differences were seen between responder and non-responder splenic tissue.Findings were supported by traditional immunostaining methods.Conclusions:While most studies in biomarkers for immunotherapy focus on tumor microenvironment,we show that benign lymph node microenvironment may predict response to immunotherapy.In responding patients,bystander lymph nodes appear to have been mobilized,resulting in reduced cytotoxic T cells.Conversely,patients whose disease progressed on immunotherapy demonstrate higher levels of macrophages that express increased PD-L1,and activated T cells not recruited to the tumor site.展开更多
Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis p...Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis process mediated by caspase-1,is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.To address these issues,hexahistidine(His6)-metal assembly(HmA)was employed as the drug delivery vector to load nigericin(Nig)and decitabine(DAC)affording a dual-drug delivery system(Nig^(+)DAC)@HmA.The(Nig^(+)DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis,easily escape from the lysosome,and are highly distributed in the tumor sites.DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome and caspase-1 protein activated by Nig.Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.Our results suggest that such an easy-to-manipulate self-assembled nano-system(Nig^(+)DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.展开更多
It is widely recognized that tumor immune microenvironment(TIME)plays a crucial role in tumor progression,metastasis,and therapeutic response.Despite several noninvasive strategies have emerged for cancer diagnosis an...It is widely recognized that tumor immune microenvironment(TIME)plays a crucial role in tumor progression,metastasis,and therapeutic response.Despite several noninvasive strategies have emerged for cancer diagnosis and prognosis,there are still lack of efective radiomic-based model to evaluate TIME status,let alone predict clinical outcome and immune checkpoint inhibitor(ICIs)response for hepatocellular carcinoma(HCC).In this study,we developed a radiomic model to evaluate TIME status within the tumor and predict prognosis and immunotherapy response.A total of 301 patients who underwent magnetic resonance imaging(MRI)examinations were enrolled in our study.The intra-tumoral expression of 17 immune-related molecules were evaluated using co-detection by indexing(CODEX)technology,and we construct Immunoscore(IS)with the least absolute shrinkage and selection operator(LASSO)algorithm and Cox regression method to evaluate TIME.Of 6115 features extracted from MRI,fve core features were fltered out,and the Radiomic Immunoscore(RIS)showed high accuracy in predicting TIME status in testing cohort(area under the curve=0.753).More importantly,RIS model showed the capability of predicting therapeutic response to anti-programmed cell death 1(PD-1)immunotherapy in an independent cohort with advanced HCC patients(area under the curve=0.731).In comparison with previously radiomicbased models,our integrated RIS model exhibits not only higher accuracy in predicting prognosis but also the potential guiding signifcance to HCC immunotherapy.展开更多
基金supported by grants from the Special Funding of China Postdoctoral Science Foundation(No.2022TQ0389)the National Natural Science Foundation of China(No.82303693)the National Postdoctoral Program for Innovative Talents(No.BX2021386)。
文摘Background:Published clinical trials have yielded controversial findings regarding the effects of sex on the benefits of immune checkpoint inhibitors(ICIs).Sex-associated differences in the efficacy of immunotherapy remain an important,unresolved question.Methods:We investigated sex-biased molecular profiles across a multitude of biomarkers linked to immunotherapy responses.Multiomics data from major solid tumors in The Cancer Genome Atlas,with sufficient sample sizes(≥50 patients of each sex),were analyzed.Ninety-five molecular markers characterizing 4 distinct aspects of the tumor immune system were summarized and compared.The inverse probability of weights algorithm was used to generate well-balanced sex subgroups.Results:Our results showed that lung squamous cell carcinoma(LUSC),pancreatic adenocarcinoma,and liver hepatocellular carcinoma were the top 3 cancer types with extensive sex-biased biomarker profiles(31/95,15/95,and 14/95,respectively).Notably,although both were categorized as non–small cell lung carcinoma,LUSC harbored significantly more sex-biased immunological features than those of lung adenocarcinoma(p<0.01).We further explored the validity of this finding by analyzing ICI-responsive signatures and individual patient-level data for non–small cell lung carcinoma and found that sex had significant interaction effects on immunotherapy outcomes in LUSC(p_(interaction)<0.05),with women tending to derive greater benefits from ICIs than men.However,this difference was not apparent in the lung adenocarcinoma group(p_(interaction)=0.66),with men and women deriving comparable benefits.Conclusions:We systematically characterized sex-biased profiles of key molecular biomarkers predicting immunotherapy responses across solid tumors,which could pave the way for individualized therapeutic approaches for men and women.
基金supported by the Bio&Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science and ICT(2021R1A2C2094629 and 2017M3A9E9072669 to Hye Ryun Kim,and 2018R1A5A2025079,2022M3A9F3016364,and 2022R1A2C1092062 to Insuk Lee)supported in part by Brain Korea 21(BK21)FOUR program+1 种基金supported by the Technology Innovation Program(20022947)funded by the Ministry of Trade Industry&Energy(MOTIE,Korea)supported by the Yonsei Fellow Program,funded by Lee Youn Jae.
文摘Lung cancer remains the leading cause of cancer death in 2024,with∼80%being non-small cell lung cancer(NSCLC).Anaplastic lymphoma kinase(ALK)rearrangements occur in∼5%of NSCLC cases,typically treated with ALK inhibitors,though resistance often develops[1].Immunotherapy has been explored for advanced or resistant ALK-positive NSCLC,but immune checkpoint blockade(ICB)treatments have shown limited clinical benefits[1].
文摘Aim:This study aimed to develop an m6A-related gene signature for predicting the prognosis of clear cell renal cell carcinoma(ccRCC)patients and explore its value in predicting the immunotherapy response.Methods:In total,530 ccRCC patients with gene expression data in the TCGA cohort were included and classified into the training(n=371)and validation(n=159)sets.Differential expression analyses of 23 m6A regulators between survivors and non-survivors were performed.Subsequently,an m6A-related gene signature was developed via LASSO Cox regression.All patients were categorized into two groups of m6A subtypes,i.e.,low or high m6A score group.The Kaplan-Meier survival curves and Tumor Immune Dysfunction and Exclusion(TIDE)scores of the two m6A subtype groups were compared to measure the gene signature’s predictive value in prognosis and potential immunotherapy response,respectively.Results:Eighteen m6A regulators were significantly differentially expressed between the survivors and non-survivors,and were also related to overall survival(OS).A gene signature containing five selected m6A methylation regulators(KIAA1429,METTL14,IGF2BP2,IGF2BP3,and SRSF2)was developed and showed favorable discrimination in the training(C-index 0.708)and validation(C-index 0.689)sets.Patients with low m6A scores had significantly better OS and lower TIDE scores than those with high m6A scores.Moreover,a robust MRI-based radiomic signature was developed to noninvasively predict the m6A subtype for each patient.Conclusion:We demonstrated the prognostic value of five m6A regulators and constructed a gene signature for prognosis and immunotherapy response prediction among ccRCC patients.In addition,a radiomic signature was developed for noninvasive prediction of the m6A subtype.These findings may promote precision medicine and provide novel insights into the regulation of tumor immune microenvironment.
文摘Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking tumors5 immune evasion will re-activate the host immune systems to eliminate tumors.Immune-checkpoint therapy(ICT)which applies anti-PD-l/PD-Ll or anti-CTLA4 treatment has been a remarkable success in the past few years.However,〜70%of patients cannot gain any clinical benefits from ICT treatment due to the tumorimmunity system's complexity・In the past,germline pathogenic variants have been thought to have only minorheritable contributions to cancer.Results:Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system.The functional components of the immune system are encoded by the host genome,thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response.Indeed,recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by(i)shaping tumor somatic mutations,altering methylation patterns and antigen-presentation capacity or(ii)influencing NK cell's function to modulate lymphocyte infiltration in the tumor microenvironment.In addition,the HLA(types A,B or C)genotypes also shape the landscape of tumor somatic mutations.Conclusion:These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.
基金funded by grants from the National Natural Science Foundation of China(grant numbers:82002664,81872074,81772740,82173345 and 82373154)the Hanghai Jiading District Health Commission Scientific Research Project Youth Fund(grant num-ber:2020-QN-02)the Meng Chao Talent Training Plan-Youth Re-search Talent Training Program of Eastern Hepatobiliary Surgery Hos-pital and the Foundation for Distinguished Youths of Jiangsu Province(grant number:BK20200006).
文摘Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.
基金supported by the Hainan Provincial Natural Science Foundation of China(Grant No.821MS137)the Innovative Research Project of Hainan Graduate Students(Grant No.Qhyb2021-58).
文摘Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis.The role of olfactory signaling pathway-related genes(OSPRGs)in glioma has not been fully elucidated.In this study,we aimed to investigate the role and relationship between OSPRGs and glioma.Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts,and the target gene(G Protein Subunit Alpha L,GNAL)was screened.The association of GNAL expression with clinicopathological characteristics,gene mutation landscape,tumor immune microenvironment(TIME),deoxyribonucleic acid(DNA)methylation,and naris-occlusion controlled genes(NOCGs)was performed.Immunohistochemistry was used to evaluate GNAL level in glioma.Further analysis was conducted to evaluate the drug sensitivity,immunotherapy response,and functional enrichment of GNAL.GNAL was an independent prognostic factor,and patients with low GNAL expression have a poor prognosis.Expression of GNAL was closely associated with clinicopathological characteristics,DNA methylation,and several immune-related pathways.Immune infiltration analysis indicated that GNAL levels were negatively correlated with immune scores.GNAL low-expression group showed efficacy with anti-PD-1 therapy.Ten compounds with significantly different half-maximal inhibitory concentration(IC50)values between the GNAL high and low-expression groups were identified.Furthermore,its expression was associated with several immune cells,immune-related genes,and NOCGs.The expression of GNAL is closely associated with clinicopathological characteristics,TIME,and the response to therapeutic interventions,highlighting its potential as a prognostic biomarker for glioma.
文摘Introduction:Benign lymph nodes have been considered the hubs of immune surveillance in cancer patients.The microenvironment of these lymphoid tissues can be immune suppressed,hence allowing for tumor progression.Understanding the spectrum of benign findings in bystander lymph nodes in immune checkpoint blockade therapy could prove to be key to understanding the mechanism and assessing treatment response.Methods:Benign lymph nodes and spleen were evaluated from patients treated with immunotherapy who subsequently received postmortem examination.We used quantitative immunofluorescence(QIF)to assess tumor infiltrating lymphocytes(TIL)and macrophage marker expression and characterized activation status using a novelmultiplexed QIF assay including CD3,GranzymeB,and Ki67.We performedimmunohistochemistry to correlate results of QIF.Results:Benign lymph nodes from non-responders to immunotherapy showed significantly higher expression of cytotoxic markers and proliferation index(Ki67)in T cells compared to responders.Higher expression of PD-L1 in macrophages was also observed.There was no significant difference in CD3+expression,but higher levels of CD8+T cells as well as CD20+B cells were seen in lymph nodes of non-responders.No significant differences were seen between responder and non-responder splenic tissue.Findings were supported by traditional immunostaining methods.Conclusions:While most studies in biomarkers for immunotherapy focus on tumor microenvironment,we show that benign lymph node microenvironment may predict response to immunotherapy.In responding patients,bystander lymph nodes appear to have been mobilized,resulting in reduced cytotoxic T cells.Conversely,patients whose disease progressed on immunotherapy demonstrate higher levels of macrophages that express increased PD-L1,and activated T cells not recruited to the tumor site.
基金This work was financially supported by the National Nature Science Foundation of China(No.21671150,52073145,21877084)the Key Research Projects of Guangdong Province(NO.2021ZDZX4019).
文摘Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis process mediated by caspase-1,is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.To address these issues,hexahistidine(His6)-metal assembly(HmA)was employed as the drug delivery vector to load nigericin(Nig)and decitabine(DAC)affording a dual-drug delivery system(Nig^(+)DAC)@HmA.The(Nig^(+)DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis,easily escape from the lysosome,and are highly distributed in the tumor sites.DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome and caspase-1 protein activated by Nig.Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.Our results suggest that such an easy-to-manipulate self-assembled nano-system(Nig^(+)DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.
基金National Natural Science Foundation of China(U21A20376,81988101,81790633 and 81830054)National Science Foundation of Shanghai(21XD1404600,17ZR143800,21JC1406600 and 22140901000)Project of Shanghai Municipal Commission of Health(2022LJ024).
文摘It is widely recognized that tumor immune microenvironment(TIME)plays a crucial role in tumor progression,metastasis,and therapeutic response.Despite several noninvasive strategies have emerged for cancer diagnosis and prognosis,there are still lack of efective radiomic-based model to evaluate TIME status,let alone predict clinical outcome and immune checkpoint inhibitor(ICIs)response for hepatocellular carcinoma(HCC).In this study,we developed a radiomic model to evaluate TIME status within the tumor and predict prognosis and immunotherapy response.A total of 301 patients who underwent magnetic resonance imaging(MRI)examinations were enrolled in our study.The intra-tumoral expression of 17 immune-related molecules were evaluated using co-detection by indexing(CODEX)technology,and we construct Immunoscore(IS)with the least absolute shrinkage and selection operator(LASSO)algorithm and Cox regression method to evaluate TIME.Of 6115 features extracted from MRI,fve core features were fltered out,and the Radiomic Immunoscore(RIS)showed high accuracy in predicting TIME status in testing cohort(area under the curve=0.753).More importantly,RIS model showed the capability of predicting therapeutic response to anti-programmed cell death 1(PD-1)immunotherapy in an independent cohort with advanced HCC patients(area under the curve=0.731).In comparison with previously radiomicbased models,our integrated RIS model exhibits not only higher accuracy in predicting prognosis but also the potential guiding signifcance to HCC immunotherapy.
