Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
文摘目的:初步探讨慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)患者外周血共抑制分子T细胞免疫球蛋白和ITIM结构域(T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain,TIGIT)和程序性细胞死亡受体1(programmed cell death protein 1,PD-1)在Tfh细胞上的表达变化特点及临床意义。方法:采用流式细胞术检测50例CLL患者、36例非CLL的慢性B淋巴细胞增殖疾病患者和30例健康者外周血Tfh细胞百分比和Tfh细胞上PD-1和TIGIT的水平,比较3组受试者的差异。分析CLL患者TIGIT+PD-1+Tfh细胞百分比与IPI评分分层的关系,以及与免疫球蛋白的相关性。结果:(1)与对照组比较,初诊CLL患者Tfh、PD-1+Tfh、TIGIT+Tfh、TIGIT+PD-1+Tfh、TIGIT+PD-1-Tfh和TIGIT-PD-1+Tfh细胞百分比明显增高,差异有统计学意义(P<0.05)。(2)TIGIT+PD-1+Tfh细胞在CLL-IPI预后分层低危组、中危组、高危组、极高危组比较分析结果,组间和组内两两比较差异均有统计学意义(P<0.05),随着预后分层增加TIGIT+PD-1+Tfh细胞水平逐渐增加。(3)受试者工作特征曲线结果显示,TIGIT+PD-1+Tfh细胞在CLL患者和非CLL患者的鉴别诊断中具有一定的诊断价值(P<0.05)。(4)Logistic回归分析显示,TIGIT+PD-1+Tfh细胞百分比是CLL发病的独立危险因素(P<0.05)。(5)CLL患者外周血中TIGIT+PD-1+Tfh与IgA、IgM、IgG均呈负相关(P<0.05)。结论:初诊CLL患者外周血TIGIT+PD-1+Tfh细胞百分比明显增加,Tfh细胞高表达共抑制分子TIGIT和PD-1参与CLL疾病的发生,并且与疾病的免疫球蛋白水平降低有关。
