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Clinical Research on the Mechanisms Underlying Immune Checkpoints and Tumor Metastasis.

ABSTRACT: This study highlights aspects of the latest clinical research conducted on the relationship between immune checkpoints and tumor metastasis. The overview of each immune checkpoint is divided into the following three sections: 1) structure and expression; 2) immune mechanism related to tumor metastasis; and 3) clinical research related to tumor metastasis. This review expands on the immunological mechanisms of 17 immune checkpoints, including TIM-3, CD47, and OX-40L, that mediate tumor metastasis; evidence shows that most of these immune checkpoints are expressed on the surface of T cells, which mainly exert immunomodulatory effects. Additionally, we have summarized the roles of these immune checkpoints in the diagnosis and treatment of metastatic tumors, as these checkpoints are considered common predictors of metastasis in various cancers such as prostate cancer, non-Hodgkin lymphoma, and melanoma. Moreover, certain immune checkpoints can be used in synergy with PD-1 and CTLA-4, along with the implementation of combination therapies such as LIGHT-VTR and anti-PD-1 antibodies. Presently, most monoclonal antibodies generated against immune checkpoints are under investigation as part of ongoing preclinical or clinical trials conducted to evaluate their efficacy and safety to establish a better combination treatment strategy; however, no significant progress has been made regarding monoclonal antibody targeting of CD28, VISTA, or VTCN1. The application of immune checkpoint inhibitors in early stage tumors to prevent tumor metastasis warrants further evidence; the immune-related adverse events should be considered before combination therapy. This review aims to elucidate the mechanisms of immune checkpoint and the clinical progress on their use in metastatic tumors reported over the last 5 years, which may provide insights into the development of novel therapeutic strategies that will assist with the utilization of various immune checkpoint inhibitors.

SUBMITTER: Tang XY

PROVIDER: S-EPMC8339928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α (HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1α inhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

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Clinical Research on the Mechanisms Underlying Immune Checkpoints and Tumor Metastasis.

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