Hypoxia May Enhance the Body's Immune System To Fight Cancer

Researchers from the Epigenetics and Immune Disease lab at the Josep Carreras Leukaemia Research Institute have found evidence that low oxygen levels in tumors could actually enhance some of the body’s immune responses against cancer, in contrast with the general paradigm that hypoxia exclusively helps cancer progression. Their findings identified a macrophage subpopulation displaying more potent immune responses under low oxygen concentrations in tumors.

In the complex landscape of cancer, tumors create their own microenvironment, often marked by low oxygen levels, a condition known as hypoxia. Hypoxia arises as tumors grow rapidly, outpacing their blood supply due to the lack of an efficient vascular system within the tumor. This oxygen-starved environment forces cancer cells and surrounding tissues to adapt in ways that typically promote tumor survival and growth.

This is also the case for the immune cells already in the tumor microenvironment, that are taught by cancer cells to tolerate them and even promote cancer growth, failing to comply with its main job. Therefore, hypoxia is generally associated with more aggressive cancers and poor patient outcomes, as it drives changes that make tumors more resistant to treatment.

This well-established paradigm is not absolute, however. Recently, Dr. Esteban Ballestar's group at the Josep Carreras Institute has published a study in the journal Science Advances reporting the identification and characterization of an immune cell population that, under hypoxia, is more effective in their responses against cancer cells. Such immune cell population is characterized by certain epigenetic alterations and the participation of a specific group of factors that contribute to the acquisition of such features.

This surprising discovery expands our understanding of the effects of hypoxia in cancer. While hypoxia is known for contributing to cancer progression, this new study reveals that at least part of the body’s immune system can fight back. The research focused on macrophages, a type of immune cell critical for maintaining tissue health and fighting infections.

In the tumor microenvironment, macrophages are usually reprogrammed to suppress the immune system, leading to worse outcomes for patients. However, this study found that, when exposed to hypoxia, some macrophages undergo significant changes that actually enhance their ability to trigger an immune response against tumors.

Specifically, the researchers have identified a group of genes linked to inflammation that become more active in hypoxic macrophages, driven by key regulatory molecules like NF-κB and HIF1α. In both bladder and ovarian cancers, tumors with these hypoxic, inflammation-boosting macrophages showed better patient outcomes.

This research challenges the traditional view that low oxygen levels in tumors only contribute to cancer progression. Instead, it highlights a potential new strategy to harness the body’s own immune system to fight cancer more effectively.

Reference:

Calle-Fabregat C, Calafell-Segura J, Gardet M, et al. NF-κB and TET2 promote macrophage reprogramming in hypoxia that overrides the immunosuppressive effects of the tumor microenvironment. Sci. Adv. 2024. doi: 10.1126/sciadv.adq5226

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