Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.
Ma J., Al Moussawi K., Lou H., Chan HF., Wang Y., Chadwick J., Phetsouphanh C., Slee EA., Zhong S., Leissing TM., Roth A., Qin X., Chen S., Yin J., Ratnayaka I., Hu Y., Louphrasitthiphol P., Taylor L., Bettencourt PJG., Muers M., Greaves DR., McShane H., Goldin R., Soilleux EJ., Coleman ML., Ratcliffe PJ., Lu X.
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.