Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Carolina J. Garcia Garcia; Yanqing Huang; Natividad R. Fuentes; Madeleine C. Turner; Maria E. Monberg; Daniel Lin; Nicholas D. Nguyen; Tara N. Fujimoto; Jun Zhao; Jaewon J. Lee; Vincent Bernard; Meifang Yu; Abagail M. Delahoussaye; Iancarlos Jimenez Sacarello; Emily G. Caggiano; Jae L. Phan; Amit Deorukhkar; Jessica M. Molkentine; Dieter Saur; Anirban Maitra; Cullen M. Taniguchi

doi:10.1053/j.gastro.2022.02.024

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Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Journal article

Peer reviewed

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Carolina J. Garcia Garcia, Yanqing Huang, Natividad R. Fuentes, Madeleine C. Turner, Maria E. Monberg, Daniel Lin, Nicholas D. Nguyen, Tara N. Fujimoto, Jun Zhao, Jaewon J. Lee, …

Gastroenterology (New York, N.Y. 1943), Vol.162(7), pp.2018-2031

06/01/2022

DOI: 10.1053/j.gastro.2022.02.024

PMID: 35216965

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Abstract

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. METHODS: We used a dual recombinase mouse model to delete Hif1 alpha or Hif2 alpha in alpha-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2 alpha expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. RESULTS: CAF-specific deletion of Hif2 alpha, but not Hif1 alpha, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

Gastroenterology & Hepatology

Life Sciences & Biomedicine

Science & Technology

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Title: Subtitle: Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment
Creators: Carolina J. Garcia Garcia - The University of Texas MD Anderson Cancer Center
Yanqing Huang - The University of Texas MD Anderson Cancer Center
Natividad R. Fuentes - The University of Texas MD Anderson Cancer Center
Madeleine C. Turner - The University of Texas MD Anderson Cancer Center
Maria E. Monberg - The University of Texas MD Anderson Cancer Center
Daniel Lin - The University of Texas MD Anderson Cancer Center
Nicholas D. Nguyen - The University of Texas MD Anderson Cancer Center
Tara N. Fujimoto - The University of Texas MD Anderson Cancer Center
Jun Zhao - The University of Texas MD Anderson Cancer Center
Jaewon J. Lee - The University of Texas MD Anderson Cancer Center
Vincent Bernard - The University of Texas MD Anderson Cancer Center
Meifang Yu - The University of Texas MD Anderson Cancer Center
Abagail M. Delahoussaye - The University of Texas MD Anderson Cancer Center
Iancarlos Jimenez Sacarello - University of Puerto Rico, Medical Sciences Campus
Emily G. Caggiano - The University of Texas MD Anderson Cancer Center
Jae L. Phan - The University of Texas MD Anderson Cancer Center
Amit Deorukhkar - The University of Texas MD Anderson Cancer Center
Jessica M. Molkentine - The University of Texas MD Anderson Cancer Center
Dieter Saur - German Cancer Research Center
Anirban Maitra - The University of Texas MD Anderson Cancer Center
Cullen M. Taniguchi - The University of Texas MD Anderson Cancer Center
Resource Type: Journal article
Publication Details: Gastroenterology (New York, N.Y. 1943), Vol.162(7), pp.2018-2031
DOI: 10.1053/j.gastro.2022.02.024
PMID: 35216965
ISSN: 0016-5085
eISSN: 1528-0012
Publisher: Elsevier
Number of pages: 14
Grant note: NIH/NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P30CA016672 / Texas Medical Center Digestive Diseases Center R01CA227517; U54CA096300 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U54CA096300/297 / Research Histology Core Laboratory F31DK121384 / Sequencing and Microarray Facility NIH Diversity Supplement; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Sidney Kimmel Foundation McNair Family Foundation RR140012 / Cancer Prevention & Research Institute of Texas (CPRIT); Cancer Prevention & Research Institute of Texas F31DK121384 / National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
Language: English
Date published: 06/01/2022
Academic Unit: Surgery
Record Identifier: 9985240990502771

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