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Review
. 2021 Apr 24;10(5):1006.
doi: 10.3390/cells10051006.

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

Zhe Fu  1   2 , Alexandra M Mowday  2   3 , Jeff B Smaill  2   3 , Ian F Hermans  1   2 , Adam V Patterson  2   3
Affiliations
Review

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

Zhe Fu et al. Cells. .

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.

Keywords: CP-506; HIF; checkpoint inhibitor; evofosfamide; hypoxia; hypoxia-activated prodrug; immune suppression; immunotherapy; oncolytic virus; tarloxotinib.

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Conflict of interest statement

The authors declare authorship of patents relating to tarloxotinib and CP-506 that are licensed or assigned by Auckland Uniservices Limited to third parties for the purpose of commercial development. The funders had no role in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Illustration of chronic and acute tumour hypoxia. Diffusion-limited hypoxia occurs when cells are located near the diffusion limit of oxygen. Perfusion-limited hypoxia arises due to temporary occlusion of tumour vasculature.
Figure 2
Figure 2
Regulation of immune response by tumour hypoxia. Different cell types by which tumour hypoxia influences in the tumour microenvironment.
Figure 3
Figure 3
General mechanism of activation of a hypoxia-activated prodrug. Hypoxia-activated prodrugs are inactive under oxygenated conditions with their reduction limited by a futile redox cycle. Upon exposure to a hypoxic environment, HAPs undergo sequential reduction steps or fragments to form either a DNA damaging agent or release a kinase inhibitor.
Figure 4
Figure 4
Modification of the hypoxic microenvironment following administration of tarloxotinib in PC9 mutant-EGFR NSCLC tumour-bearing mice. The representative immunohistochemical image shows hypoxic regions (green, pimonidazole binding) across a tumour cross section before and after (72 h) a single dose of tarloxotinib (30 mg/kg, intraperitoneal). Nuclei are counterstained (blue, DAPI). Image was provided by Dr Shevan Silva with permission.
Figure 5
Figure 5
Modification of the hypoxic microenvironment following administration of CP-506 in MDA-MB-468 TNBC tumour-bearing mice. Representative immunohistochemical image showing hypoxic regions in whole tumour cross section (green, pimonidazole, red EF5 binding) before and after (24 h) a single dose of CP-506 (900 mg/kg, intraperitoneal). Nuclei are counterstained (blue, DAPI). Image was provided by Dr Maria Abbattista with permission.
See this image and copyright information in PMC

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