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Cancer hypoxia activates immune responses

The tumour microenvironment dictates many of the hallmarks of cancer as well as anticancer immune responses. A European study investigated how the low oxygen levels of tumours affect the infiltrating immune cells.
Cancer hypoxia activates immune responses
Tumour infiltrating lymphocytes (TILs) constitute an adaptive immune response against cancer that is associated with a better survival in cancer patients. However, TILs are severely restrained in their ability to tackle tumours, and emerging evidence suggests that the low levels of oxygen availability in solid tumours induce profound changes on these cells.

In general, the response to hypoxia is regulated by the hypoxia inducible transcription factors HIF-1α and HIF-2α. Both transcription factors are oxygen sensitive and function to the physiological adaptation at the cellular, tissue and organism levels. HIF-1α is expressed in most mammalian cell types with a well-established role in both innate and adaptive immune cells, while the role of HIF-2α in the immune system is less clear.

The scope of the EU-funded HYPOXIC TILS (Influence of hypoxia in the tumor microenvironment on the adaptive immune response and cancer immunotherapy) project was to understand the role of HIF in the T cell response against cancer. To achieve this, scientists deleted HIF-1α or HIF-2α from peripheral CD8+ T cells and identified an essential role for HIF-1α, but not HIF-2α, in the control of T cell-mediated antitumour responses.

In particular, HIF-1α, but not HIF-2α was necessary for the acquisition of an effector phenotype and deletion of HIF-1α impaired the expression of molecules and cytokines critically involved in cytotoxic T cell-mediated tumour rejection. In addition, expression of the immune checkpoint inhibitor programmed cell death protein 1 (PD-1) in TILs was dependent on HIF-1α. In mouse cancer models, deletion of HIF-1α in CD8+ T lymphocytes reduced their infiltration and accelerated tumour growth.

Collectively, the findings of the HYPOXIC TILS study underscore the role of HIFs in activating anticancer adaptive immune responses. This contradicts the pharmacological inhibition of the hypoxia signalling pathway as an anticancer strategy, requiring further investigation to overcome this problem.

Related information

Keywords

Cancer, hypoxia, tumour microenvironment, immune responses, tumour infiltrating lymphocytes, HYPOXIC TILS
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