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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Ludwig Institute for Cancer Research; University of Oxford; University of Southampton; University of New South Wales Sydney; Kirby Institute; British Columbia Cancer Agency; University of British Columbia; University of British Columbia; University of London; University College London; University of Oxford; University of Oxford; Jenner Institute; Universidade de Lisboa; Universidade Catolica Portuguesa; Imperial College London; University of Cambridge; University of Birmingham
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10055
• DOI: 10.1073/pnas.2309957121
• 发表日期: 2024-03-05
• 关键词: colorectal-cancer; macrophages; expression; hypoxia; fih-1; hif-1-alpha; activation; suppressor; GROWTH; cells

摘要

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.