Many tumors depend on the hypoxia inducible factor (HIF) for their survival, and several drugs that inhibit HIF signaling have been approved for cancer therapy. A study published in PNAS in February, led by Ludwig Oxford alumnus Jingyi Ma, Director Xin Lu and Distinguished Scholar Peter Ratcliffe explored how a well-characterized cellular regulator of HIF, factor inhibiting HIF (FIH), influences tumor growth. The researchers reported that both copies of the FIH gene are required to prevent the development of spontaneous mouse B cell lymphomas, especially pulmonary B cell lymphoma, during the aging process. FIH deficiency alters the immune composition in aged mice and induces a tumor-promoting immune microenvironment through the manipulation of myeloid cell function: FIH-defective myeloid cells acquire tumor supportive properties in response to environmental cues from cancer cells or cancer-associated inflammation. These properties include enhanced migration into tumors and higher expression of the enzyme arginase, which breaks down arginine, an amino acid essential to T cell activation. Increased levels of arginase reduce T cell proliferation and promote tumor growth. Notably, the FIH-deficient environment could influence the behavior and growth of injected cancer cells in what can be called an “outside-in” model—highlighting the importance of the external microenvironment on tumor growth.
Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment
PNAS, 2024 February 29