肿瘤特异性CD8+T细胞分化及调控机制的研究进展

Research Progress in the Differentiation and Regulatory Mechanisms of Tumor Specific CD8+T Cell

关键词:  肿瘤特异性CD8⁺T细胞  分化状态  记忆  耗竭  效应

Key words:  tumor specific CD8⁺T cells  differentiation state  memory  exhaustion  effector

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。

Abstract:

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 distinguish bystander and tumor-specific CD8⁺T cells. The expression of CD39, CD103 and CD69 on the surface of CD8⁺T cells is closely related to patient prognosis. Moreover, IL-17A and CCR6 suggest insufficient specificity for tumor cells and lower effector function. As tumor progresses, the memory and effector phenotypes of tumor specific CD8⁺T cells gradually vanish and eventually differentiate into terminally exhausted cells. Epigenetic changes and metabolic reprogramming are involved in regulating this process. The increase of chromatin accessibility of exhaustion related genes is the direct causes of the exhaustion of CD8⁺T cells. Hypoxia- or deprivation of nutrients-caused dysfunction of oxidative phosphorylation and glycolysis is one of the important causes. Moreover, the complex and diverse immunosuppressive signals within tumor microenvironment, including excess of immune checkpoint molecule, lack of co-stimulation receptor, etc. accelerate this process. Clinical studies have shown that T cell factor 1(TCF-1), CX3CR1 and CD103 are correlated to the response of patients to immunotherapy, indicating that the memory, effector phenotype, and the tumor specificity of CD8⁺T cells are the basis for their response to immunotherapy. Tumor vaccine immunization and other approaches targeting critical regulatory molecules have been proven to increase the density of tumor specific effector CD8⁺T cells effectively and are expected to become new approaches to enhance anti-tumor immune response or improve immunotherapy response. Together, this paper reviews the fate of tumor specific CD8⁺T cells after activation, the molecular markers and transcriptional regulatory molecules characterizing distinct differentiation states of CD8⁺T cells, as well as the factors that influence CD8⁺T cells differentiation, in order to provide a reference for more precise regulation of CD8⁺T cell phenotype and enhancement of anti-tumor immune response.