The regulation of immune checkpoints by the hypoxic tumor microenvironment

PeerJ

article

Min Hu¹  Yongfu Li²  Yuting Lu²  Miao Wang²  Yingrui Li¹  Chaoying Wang³  Qin Li²  Hong Zhao¹ 

[1] Department of Biochemistry & Molecular Biology, Basic Medical College, Shanxi Medical University, Taiyuan, Shanxi Province;Department of Oncology, Beijing Friendship Hospital, Capital Medical University;Department of Oncology, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province

关键词: Tumor microenvironment;    Hypoxia;    Immune checkpoints;    Immune escape;    Drug treatment;   

DOI  :  10.7717/peerj.11306

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

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.

【 授权许可】

CC BY