Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy

Abstract

The magnitude of the host immune response can be regulated by either stimulatory or inhibitory immune checkpoint molecules. Receptor-ligand binding between inhibitory molecules is often exploited by tumours to suppress anti-tumour immune responses. Immune checkpoint inhibitors that block these inhibitory interactions can relieve T-cells from negative regulation, and have yielded remarkable activity in the clinic. Despite this success, clinical data reveal that durable responses are limited to a minority of patients and malignancies, indicating the presence of underlying resistance mechanisms. Accumulating evidence suggests that tumour hypoxia, a pervasive feature of many solid cancers, is a critical phenomenon involved in suppressing the anti-tumour immune response generated by checkpoint inhibitors. In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness.

Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification

“…Targeting hypoxia to enhance the efficacy of immunotherapy is underway [ 45 ]. Unlike previous immunotherapies that did not consider the hypoxic tumor microenvironment, researchers have begun to explore tumor reoxygenation, hypoxia-activated prodrugs, targeting of the HIF-1 pathway, hypoxia-targeted biologicals, and metabolic intervention [ 46 , 47 ]. In addition to the aspects mentioned above, there were also some studies that offered different perspectives on the treatment of hypoxic tumor microenvironment.…”

Extracellular Vesicles—A New Potential Player in the Immunology of Renal Cell Carcinoma

“…Hypoxia-induced stabilization of HIF-1 has been shown to promote multiple immunosuppressive mechanisms within the TME. Examples are the promotion of Treg formation and recruitment, upregulation of PD-L1, CTLA-4, and LAG-3 to induce T-cell anergy and tolerance, recruitment of suppressive MDSCs and M2-like macrophages, the blocking of DC and NK-cell functions, suppression of T-cell activity through the accumulation of extracellular adenosine, etc., reviewed in [ 57 ].…”

Hypoxia-inducible factor-1α inhibition augments efficacy of programmed cell death 1 antibody in murine prostatic cancer models

“…Low oxygen is commonly found in solid tumors [5]. Tumor cells induce hypoxia through various mechanisms, such as high metabolic rate and high oxygen consumption, which cause endothelial dysfunction or damage the delivery of oxygen due to various effects on blood vessels [6], create a chronic hypoxia environment, activate the hypoxia-inducible factor (HIF) signaling pathway [7], accelerate tumor growth, improve tumor invasiveness, and promote tumor metastasis.…”