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

in Proceedings of the National Academy of Sciences of the United States of America by Jingyi Ma, Khatoun Al Moussawi, Hantao Lou, Hok Fung Chan, Yihua Wang, Joseph Chadwick, Chansavath Phetsouphanh, Elizabeth A Slee, Shan Zhong, Thomas M Leissing, Andrew Roth, Xiao Qin, Shuo Chen, Jie Yin, Indrika Ratnayaka, Yang Hu, Pakavarin Louphrasitthiphol, Lewis Taylor, Paulo J G Bettencourt, Mary Muers, David R Greaves, Helen McShane, Robert Goldin, Elizabeth J Soilleux, Mathew L Coleman, Peter J Ratcliffe, Xin Lu

TLDR

  • FIH is a protein that helps regulate the growth of tumors. The study found that FIH is a haploinsufficient suppressor of spontaneous B cell lymphomas, which are a type of cancer that affects the immune system. FIH deficiency alters the immune system in aging mice and creates a tumor-supportive environment. FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Abstract

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.

Overview

  • The study investigates the role of factor-inhibiting HIF (FIH) in regulating tumor development under physiological conditions. FIH is a negative regulator of hypoxia-inducible factor (HIF) and has been approved as a cancer treatment strategy. The study aims to understand how FIH may affect tumor growth and immune composition in aging mice. The methodology used includes the use of syngeneic mouse tumor models and the analysis of immune composition in FIH-deficient mice. The primary objective of the study is to determine the role of FIH in maintaining immune homeostasis and suppressing tumorigenesis through a cell-extrinsic pathway.

Comparative Analysis & Findings

  • The study found that FIH-deficient 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. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. The study also found that FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Implications and Future Directions

  • The study's findings suggest that FIH may be a potential target for cancer treatment strategies that target the immune system. The study also highlights the importance of understanding the role of regulators of HIF in maintaining immune homeostasis and suppressing tumorigenesis. Future research could explore the use of FIH inhibitors in combination with other cancer treatment strategies to enhance their efficacy. The study also highlights the need for further research to understand the mechanisms underlying the tumor-supportive immune environment created by FIH deficiency and to identify potential therapeutic targets for modulating this environment.
Read Full Article