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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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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (10), p.e2309957121-e2309957121 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1073/pnas.2309957121 |
| format | article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2309957121</identifier><identifier>PMID: 38422022</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2024-03, Vol.121 (10), p.e2309957121-e2309957121</ispartof><rights>Copyright National Academy of Sciences Mar 5, 2024</rights><rights>Copyright © 2024 the Author(s). 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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. 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PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2024-03-05</date><risdate>2024</risdate><volume>121</volume><issue>10</issue><spage>e2309957121</spage><epage>e2309957121</epage><pages>e2309957121-e2309957121</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2024-03, Vol.121 (10), p.e2309957121-e2309957121 |
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| 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 |
| title | Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment |
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