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

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 p...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (10), p.e2309957121-e2309957121
Main Authors: Ma, Jingyi, Al Moussawi, Khatoun, Lou, Hantao, Chan, Hok Fung, Wang, Yihua, Chadwick, Joseph, Phetsouphanh, Chansavath, Slee, Elizabeth A, Zhong, Shan, Leissing, Thomas M, Roth, Andrew, Qin, Xiao, Chen, Shuo, Yin, Jie, Ratnayaka, Indrika, Hu, Yang, Louphrasitthiphol, Pakavarin, Taylor, Lewis, Bettencourt, Paulo J G, Muers, Mary, Greaves, David R, McShane, Helen, Goldin, Robert, Soilleux, Elizabeth J, Coleman, Mathew L, Ratcliffe, Peter J, Lu, Xin
Format: Article
Language:English
Subjects:
Animal models
Animals
Arginase
B-cell lymphoma
Biological Sciences
Cancer
Cancer therapies
Cell culture
Homeostasis
Hypoxia
Hypoxia - metabolism
Hypoxia-inducible factors
Lymphoma, B-Cell
Mice
Mixed Function Oxygenases - metabolism
Myeloid cells
Physiological effects
Physiology
Repressor Proteins - metabolism
Tumor Microenvironment
Tumorigenesis
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2309957121