Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment

Journal article

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Authors: Ma, J; Al Moussawi, K; Lou, H; Chan, HF; Wang, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences
• Volume: 121
• Issue: 10
• Article number: e2309957121
• Publication date: 2024-02-29
• Acceptance date: 2024-01-03
• DOI: 10.1073/pnas.2309957121
• EISSN: 1091-6490
• ISSN: 0027-8424
• Pmid: 38422022
• Language: English
• Keywords: tumor microenvironment; hypoxia; b-cell; lymphoma; mixed function oxygenases; repressor proteins