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

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.