The regulation of immune checkpoints by the hypoxic tumor microenvironment

Abstract

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.

Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment

“…As previously discussed, HIF-1α- mediates adenosine accumulation within the TME (due to upregulation of enzymes CD39 and CD73). This activates the adenosine receptor A2aR on tumour cells and CD8+ T-cells which subsequently upregulates their PD-1 and CTLA-4 expression [ 307 ]. CD8+ T-cells also upregulate LAG3, TIM3 and PD-1 expression in response to hypoxia in a HIF-1α-dependent manner [ 308 , 309 ].…”

Immune Checkpoint Inhibitors in Cancer Therapy

“…Hypoxia is measured using specialized techniques such as PO2 electrode measurement, fibre optic probe, and nuclear magnetic resonance (NMR) [124,125]. A lack of oxygen causes hypoxia-inducible factor-1 (HIF-1), a transcription factor, to be activated within the TME, and its subunit can promote angiogenesis and metastasis [126,127]. Hypoxia has been shown to modulate the expression of immune checkpoints such as CTLA-4, CD47, PD-1/L-1, and TIM3 in order to manipulate immune cells' mediated anti-tumour response, thereby inhibiting immune surveillance [126].…”

“…A lack of oxygen causes hypoxia-inducible factor-1 (HIF-1), a transcription factor, to be activated within the TME, and its subunit can promote angiogenesis and metastasis [126,127]. Hypoxia has been shown to modulate the expression of immune checkpoints such as CTLA-4, CD47, PD-1/L-1, and TIM3 in order to manipulate immune cells' mediated anti-tumour response, thereby inhibiting immune surveillance [126]. In hypoxic conditions, the combination of adenosine and the A2a receptor increases immune checkpoint expression, resulting in T cell suppression [126].…”

“…Hypoxia has been shown to modulate the expression of immune checkpoints such as CTLA-4, CD47, PD-1/L-1, and TIM3 in order to manipulate immune cells' mediated anti-tumour response, thereby inhibiting immune surveillance [126]. In hypoxic conditions, the combination of adenosine and the A2a receptor increases immune checkpoint expression, resulting in T cell suppression [126]. Zandberg et al reported that in an animal model of HNSCC, disease control rate (DCR) and survival were altered in mice with intra-tumoral hypoxia, rendering them resistant to anti-PD-1 immunotherapy [128].…”

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

“…Expression of immune checkpoints such as programed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 are associated with poor prognosis and are often upregulated in malignant tumors. Immune checkpoint inhibitors are a promising form of immunotherapy which block the immune suppressing checkpoints displayed by cancers, which allows them to evade the immune response [ 248 ]. The success of these therapies indicates the importance of reducing immune checkpoints in cancerous cells.…”