摘要
肿瘤特异性CD8^(+)T细胞是抗肿瘤免疫应答的主要效应细胞之一,其分化状态与免疫应答强度、对免疫疗法的响应程度密切相关。在肿瘤病程中,CD8^(+)T细胞往往呈现耗竭状态,主要表现为效应功能降低和增殖能力下降。近几年,耗竭CD8^(+)T细胞的高度异质性特征备受关注,其中记忆、效应和终末耗竭表型是当下考察肿瘤特异性CD8^(+)T细胞分化状态的3个重要维度。伴随肿瘤进展,肿瘤特异性CD8^(+)T细胞的干性、效应表型逐渐丢失,最终分化为终末耗竭细胞,表观遗传学变化和代谢重编程参与调控这一过程,另外肿瘤微环境中复杂多样的免疫抑制性信号加速了这一过程的发生。本文综述了肿瘤特异性CD8^(+)T细胞激活后的命运以及不同分化状态的分子标志物和转录调控分子、影响分化状态的因素、与免疫疗法响应相关的标志物、调控CD8^(+)T细胞增强抗肿瘤作用的应用等方面近年来的研究进展,以期为更加精准地调控CD8^(+)T细胞表型,增强抗肿瘤免疫应答等研究提供参考。
Tumor specific CD8^(+)T cells are the major effector population during anti-tumor immune response,and their differentiation states are closely related to the intensity of immune response and the responsiveness to immunotherapy.During the course of cancer,CD8^(+)T cells often exhibit an exhaustion phenotype,mainly characterized by decreased effector function and proliferative capacity.In recent years,the high heterogeneity of exhausted CD8^(+)T cells have received considerable attention,with memory,effector and terminal exhaustion phenotypes being the three important dimensions for investigating the differentiation states of tumor specific CD8^(+)T cells.Exhausted CD8^(+)T cells with memory characteristics have been referred to as“memory-like”“stem-like”,or progenitor exhausted T cells.This subset can self-renew and differentiate into effector like or terminally exhausted cells,and is currently being considered as the main cell population that responds to immune checkpoint blockade.The self-renewal of these progenitor exhausted CD8^(+)T cells was found to depend on expression of TCF1.Terminal exhausted CD8^(+)T cells is characterized by the expression of several immune checkpoint molecules such as programmed cell death protein 1(PD-1),cytotoxic T lymphocyte-associated antigen 4(CTLA-4),lymphocyte activation gene(LAG),T cell immunoglobulin and mucin domain-containing protein 3(TIM3)etc.The level of PD-1 increases as the exhaustion of CD8^(+)T cells getting worse,while TIM-3 is restricted to the terminally exhausted subset.Effector CD8^(+)T cells are intermediate of the above two types,and surface receptor CX3C chemokine receptor 1(CX3CR1)is enriched in this subset.T-bet is the key transcription factor that drives the effector phenotype of tumor specific CD8^(+)T cells,while TOX is a critical driver of the exhaustion phenotype.Besides the above exhaustion states,the heterogeneity of CD8^(+)T cells are also characterized by the expression of surface receptors.For example,CD39 is an important marker to disting
作者
方堃
方艳芬
FANG Kun;FANG Yanfen(Division of Anti-tumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China)
出处
《中国现代应用药学》
CAS
CSCD
北大核心
2023年第12期1670-1679,共10页
Chinese Journal of Modern Applied Pharmacy
基金
上海市科委“科技创新行动计划”实验动物研究领域项目(21140902000)
中国科学院青年创新促进会(2020281)。
