Objective:The expression of programmed death 1(PD-1)on CD8^(+)T cells is associated with their activation and exhaustion,while CD57 serves as a senescence marker.The impact of PD-1^(+)and CD57^(+)CD8^(+)T cells on the...Objective:The expression of programmed death 1(PD-1)on CD8^(+)T cells is associated with their activation and exhaustion,while CD57 serves as a senescence marker.The impact of PD-1^(+)and CD57^(+)CD8^(+)T cells on the prognosis of patients with advanced high-grade serous ovarian cancer(HGSOC)remain unclear.Methods:We assessed the percentages of PD-1^(+)and CD57^(+)CD8^(+)T cells in tumor-infiltrating lymphocytes(TILs,n=85)and tumor ascites lymphocytes(TALs,n=87)using flow cytometry.The optimal cutoffs for these markers in TILs and TALs were determined through the log-rank maximization method.Gene expression analysis elucidated the tumor immune microenvironment(TIME,n=36).Results:Patients with higher PD-1^(+)CD8^(+)TILs(>87.8%)exhibited longer platinum-free interval(PFI)and overall survival(OS).In contrast,those with elevated CD57^(+)CD8^(+)TALs(>28.69%)were more likely to experience chemotherapy and had lower complete remission rates,shorter PFI and OS.PD-1^(+)CD8^(+)TILs are primarily displayed an effector memory state with strong proliferative and secretory capabilities.Approximately 50%of CD57^(+)CD8^(+)TALs were terminally differentiated,exhibiting significantly impaired proliferation.Based on the proportions of PD-1^(+)CD8^(+)TILs and CD57^(+)CD8^(+)TALs,patients were categorized into good,median and poor prognosis groups,with median PFI of 47.78,27.29 and 11.96 months,respectively(P<0.0001).Median OS for these groups was not reach,49.23 and 30.92 months,respectively(P<0.0001).Patients with poor prognosis exhibit significantly reduced CD8^(+)T cell proportion and increased M2 macrophage in the TIME,alongside downregulation of multiple T cell activation-related pathways.Conclusions:Lower levels of PD-1^(+)CD8^(+)TILs and higher CD57^(+)CD8^(+)TALs,assessed prior to treatment,correlated with poor prognosis and suppressive TIME in advanced HGSOC.展开更多
Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD...Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.展开更多
基金supported by National Natural Science Foundation of China(No.82372888)National Key Research and Development Program of China(No.2022YFC2704000)+6 种基金National Natural Science Foundation of China(No.82273383)the Capital’s Funds for Health Improvement and Research(No.2020-2-4098)Youth program of Beijing Municipal Natural Science Foundation(No.7204328)Clinical Medicine Plus X-Young Scholars Project,Peking University(No.PKU2022LCXQ020)Key Clinical Project of Peking University Third Hospital(No.BYSY2022050)Key Clinical Projects of Peking University Third Hospital(No.BYSYZD2021006)Key Clinical Projects of Peking University Third Hospital(No.BYSYZD2019034).
文摘Objective:The expression of programmed death 1(PD-1)on CD8^(+)T cells is associated with their activation and exhaustion,while CD57 serves as a senescence marker.The impact of PD-1^(+)and CD57^(+)CD8^(+)T cells on the prognosis of patients with advanced high-grade serous ovarian cancer(HGSOC)remain unclear.Methods:We assessed the percentages of PD-1^(+)and CD57^(+)CD8^(+)T cells in tumor-infiltrating lymphocytes(TILs,n=85)and tumor ascites lymphocytes(TALs,n=87)using flow cytometry.The optimal cutoffs for these markers in TILs and TALs were determined through the log-rank maximization method.Gene expression analysis elucidated the tumor immune microenvironment(TIME,n=36).Results:Patients with higher PD-1^(+)CD8^(+)TILs(>87.8%)exhibited longer platinum-free interval(PFI)and overall survival(OS).In contrast,those with elevated CD57^(+)CD8^(+)TALs(>28.69%)were more likely to experience chemotherapy and had lower complete remission rates,shorter PFI and OS.PD-1^(+)CD8^(+)TILs are primarily displayed an effector memory state with strong proliferative and secretory capabilities.Approximately 50%of CD57^(+)CD8^(+)TALs were terminally differentiated,exhibiting significantly impaired proliferation.Based on the proportions of PD-1^(+)CD8^(+)TILs and CD57^(+)CD8^(+)TALs,patients were categorized into good,median and poor prognosis groups,with median PFI of 47.78,27.29 and 11.96 months,respectively(P<0.0001).Median OS for these groups was not reach,49.23 and 30.92 months,respectively(P<0.0001).Patients with poor prognosis exhibit significantly reduced CD8^(+)T cell proportion and increased M2 macrophage in the TIME,alongside downregulation of multiple T cell activation-related pathways.Conclusions:Lower levels of PD-1^(+)CD8^(+)TILs and higher CD57^(+)CD8^(+)TALs,assessed prior to treatment,correlated with poor prognosis and suppressive TIME in advanced HGSOC.
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1304504)National Natural Science Foundation of China(No.82293633 and 82270180)。
文摘Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.
