As gastric cancer and colorectal cancer are leading causes of cancer death globally, present review mainly focuses on these two kinds of cancer types (90, 91)
As gastric cancer and colorectal cancer are leading causes of cancer death globally, present review mainly focuses on these two kinds of cancer types (90, 91). 4.1. then review the landscapes and mechanisms of T cell exhaustion in gastrointestinal cancer as well as clinical applications, which will provide a clear vision for the development of future immunotherapies. RKI-1313 Keywords: T cell exhaustion, gastric cancer, colorectal cancer, immune checkpoints, immunotherapy 1.?Introduction T cell exhaustion (TEX) is an effective low-response T cell state during chronic infection. This hyporeactive state is thought to be due to the inability of pathogens to be rapidly cleared in chronic inflammation and the continued stimulation of this specific T cell proliferation, resulting in the upregulation of many immune checkpoints on the surface of T cells, leading to a reduction in their proliferation and ability to capture pathogens (1, 2). Many studies have been devoted to exploring the mechanisms behind TEX, starting RKI-1313 with attempts to overcome its problems. Researchers have tried to explore how TEX causes a reduction in T cell effector function and proliferation levels, as well as leading to the expression of suppressive immune checkpoint receptors and ultimately immune escape of the tumor (3, 4). There is evidence that CD8+ T cell infiltration below 2.2% predicts a fourfold higher risk of disease progression after cancer surgery (hazard ratio (HR) = 3.84, p < 0.01), but the proportion of CD8+ T cells does not correlate with other clinical data, suggesting that the mechanisms that trigger differences in T cell heterogeneity and kinetics are unclear (5, 6). Therefore, it is particularly important to identify the molecular determinants that regulate the number, spatial distribution, and heterogeneity of CD8+ T cells KIAA1575 in tumors, which could help more patients to benefit from immunotherapy (7). Current studies on TEX have found that the mechanisms behind it may be closely related to transcription factors and epigenetic regulation (8, 9). For example, in a study using a mouse model of chronic LCMV infection, the transcription factor TCF-1 was found to promote the function of depleted CD8+ T cells by promoting the expression of a series of key effector function-related transcriptional regulators, including Foxo1, Zeb2, Id3, and Eomes (10). A study identified progressive heritable methylation programs that limit T cell expansion and clonal diversity during PD-1 blockade therapy, RKI-1313 and when these programs were reversed, TEX no longer inhibited immune checkpoint blocker (ICB) therapy (11). These findings suggest that transcription factors and epigenetic regulation may serve as biomarkers of CD8+ TEX and potential immunotherapeutic targets, which RKI-1313 would provide precision therapy for tumor immunization patients (12). The importance of TEX in tumor immunotherapy has been confirmed by many studies, however, what needs more attention is that gastrointestinal tumors are perhaps more suitable for deeper work in this direction than other tumors. For example, a pan-cancer analysis showed that the presence of a lower percentage of triminal CD8+ Tex and a higher percentage of CD8+ Trm cells in STAD tissues implies that the gastric cancer tumor microenvironment has a better composition of anti-tumor T cells, which would point to the development of more promising precision-targeted immunotherapies (3, 6, 9). There are many ongoing studies on CD8+ TEX in gastrointestinal cancers regarding immune checkpoint inhibition, CAR T cells, and synergistic therapy with chemotherapy, but many mechanisms are still unclear (13). Therefore, this review will describe the origin, function, detection modalities, and mechanisms involved in CD8+ TEX, and review TEX in gastrointestinal cancers and related clinical applications, which will provide a clear and comprehensive vision for the development of future immunotherapies. 2.?CD8+ T cell exhaustion 2.1. Origin and function of CD8+ T cell CD8+ T cells are cytotoxic T lymphocytes (CTL cells) that are produced by the body to fight against viruses, tumors, and other pathogens (14). They produce and express -T cell receptors with CD8 in the thymus and destroy them by recognizing MHC class I on target cells (15). When the bodys CD8+ T cells or function is diminished, anti-tumor immune function will decrease and the risk of tumor growth and cancer metastasis will increase (16). CD8+ T cells develop from CD34+ hematopoietic stem cells located in the bone marrow, which express CD2, CD5, and CD7 before leaving the bone marrow and entering the thymus to become CD3-expressing lymphoid progenitors, RKI-1313 and subsequently undergo a double negative (DN) (CD8-CD4-) phase and a double positive (DP) phase (CD8+ CD4+) and finally became solitary positive (SP) CD8+ thymocytes. These cells are selected by positive and negative clones to become CD8+ T- cells and are.