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

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

doi:10.1073/pnas.2309957121

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

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 MuersDavid R. Greaves, Helen McShane, Robert Goldin, Elizabeth J. Soilleux, Mathew L. Coleman, Peter J. Ratcliffe, Xin Lu

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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.

Original language	English
Article number	e2309957121
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	121
Issue number	10
DOIs	https://doi.org/10.1073/pnas.2309957121
Publication status	Published - 29 Feb 2024

Keywords

Tumor microenvironment
Hypoxia-inducible factor
Factor-inhibiting HIF
B cell lymphoma
Tumor suppression

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.2309957121Licence: CC BY

94989475Final published version, 4.92 MBLicence: CC BY

http://hdl.handle.net/10400.14/44141Licence: CC BY

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Ma, J., Moussawi, K. A., Lou, H., Chan, H. F., Wang, Y., Chadwick, J., Phetsouphanh, C., Slee, E. A., Zhong, S., Leissing, T. M., Roth, A., Qin, X., Chen, S., Yin, J., Ratnayaka, I., Hu, Y., Louphrasitthiphol, P., Taylor, L., Bettencourt, P. J. G., ... Lu, X. (2024). Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment. Proceedings of the National Academy of Sciences of the United States of America, 121(10), Article e2309957121. https://doi.org/10.1073/pnas.2309957121

@article{1fd1518a2e3f48bf89bc082fcd67b476,

title = "Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment",

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.",

keywords = "Tumor microenvironment, Hypoxia-inducible factor, Factor-inhibiting HIF, B cell lymphoma, Tumor suppression",

author = "Jingyi Ma and Moussawi, {Khatoun Al} and Hantao Lou and Chan, {Hok Fung} and Yihua Wang and Joseph Chadwick and Chansavath Phetsouphanh and Slee, {Elizabeth A.} and Shan Zhong and Leissing, {Thomas M.} and Andrew Roth and Xiao Qin and Shuo Chen and Jie Yin and Indrika Ratnayaka and Yang Hu and Pakavarin Louphrasitthiphol and Lewis Taylor and Bettencourt, {Paulo J. G.} and Mary Muers and Greaves, {David R.} and Helen McShane and Robert Goldin and Soilleux, {Elizabeth J.} and Coleman, {Mathew L.} and Ratcliffe, {Peter J.} and Xin Lu",

note = "Publisher Copyright: {\textcopyright} 2024 the Author(s). Published by PNAS.",

year = "2024",

month = feb,

day = "29",

doi = "10.1073/pnas.2309957121",

language = "English",

volume = "121",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Ma, J, Moussawi, KA, 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 2024, 'Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 10, e2309957121. https://doi.org/10.1073/pnas.2309957121

TY - JOUR

T1 - Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment

AU - Ma, Jingyi

AU - Moussawi, Khatoun Al

AU - Lou, Hantao

AU - Chan, Hok Fung

AU - Wang, Yihua

AU - Chadwick, Joseph

AU - Phetsouphanh, Chansavath

AU - Slee, Elizabeth A.

AU - Zhong, Shan

AU - Leissing, Thomas M.

AU - Roth, Andrew

AU - Qin, Xiao

AU - Chen, Shuo

AU - Yin, Jie

AU - Ratnayaka, Indrika

AU - Hu, Yang

AU - Louphrasitthiphol, Pakavarin

AU - Taylor, Lewis

AU - Bettencourt, Paulo J. G.

AU - Muers, Mary

AU - Greaves, David R.

AU - McShane, Helen

AU - Goldin, Robert

AU - Soilleux, Elizabeth J.

AU - Coleman, Mathew L.

AU - Ratcliffe, Peter J.

AU - Lu, Xin

PY - 2024/2/29

Y1 - 2024/2/29

N2 - 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.

AB - 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.

KW - Tumor microenvironment

KW - Hypoxia-inducible factor

KW - Factor-inhibiting HIF

KW - B cell lymphoma

KW - Tumor suppression

UR - http://www.scopus.com/inward/record.url?scp=85186308201&partnerID=8YFLogxK

U2 - 10.1073/pnas.2309957121

DO - 10.1073/pnas.2309957121

M3 - Article

C2 - 38422022

SN - 0027-8424

VL - 121

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 10

M1 - e2309957121

ER -

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

Abstract

Keywords

UN SDGs

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CIIS: Center for Interdisciplinary Research in Health

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

CIIS: Center for Interdisciplinary Research in Health

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