Carolina J Garcia Garcia1, Yanqing Huang2, Natividad R Fuentes2, Madeleine C Turner2, Maria E Monberg3, Daniel Lin2, Nicholas D Nguyen2, Tara N Fujimoto2, Jun Zhao3, Jaewon J Lee3, Vincent Bernard4, Meifang Yu2, Abagail M Delahoussaye2, Iancarlos Jimenez Sacarello5, Emily G Caggiano6, Jae L Phan2, Amit Deorukhkar2, Jessica M Molkentine2, Dieter Saur7, Anirban Maitra3, Cullen M Taniguchi8. 1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center Houston, Texas; School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico. 2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4. UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center Houston, Texas; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico. 6. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center Houston, Texas. 7. Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany. 8. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: ctaniguchi@mdanderson.org.
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 Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α 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 Hif2α, but not Hif1α, 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.
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 Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α 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 Hif2α, but not Hif1α, 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.
Authors: Andrew D Rhim; Paul E Oberstein; Dafydd H Thomas; Emily T Mirek; Carmine F Palermo; Stephen A Sastra; Erin N Dekleva; Tyler Saunders; Claudia P Becerra; Ian W Tattersall; C Benedikt Westphalen; Jan Kitajewski; Maite G Fernandez-Barrena; Martin E Fernandez-Zapico; Christine Iacobuzio-Donahue; Kenneth P Olive; Ben Z Stanger Journal: Cancer Cell Date: 2014-05-22 Impact factor: 31.743
Authors: Mara H Sherman; Ruth T Yu; Tiffany W Tseng; Cristovao M Sousa; Sihao Liu; Morgan L Truitt; Nanhai He; Ning Ding; Christopher Liddle; Annette R Atkins; Mathias Leblanc; Eric A Collisson; John M Asara; Alec C Kimmelman; Michael Downes; Ronald M Evans Journal: Proc Natl Acad Sci U S A Date: 2017-01-17 Impact factor: 11.205
Authors: Wenfang Chen; Haley Hill; Alana Christie; Min Soo Kim; Eboni Holloman; Andrea Pavia-Jimenez; Farrah Homayoun; Yuanqing Ma; Nirav Patel; Paul Yell; Guiyang Hao; Qurratulain Yousuf; Allison Joyce; Ivan Pedrosa; Heather Geiger; He Zhang; Jenny Chang; Kevin H Gardner; Richard K Bruick; Catherine Reeves; Tae Hyun Hwang; Kevin Courtney; Eugene Frenkel; Xiankai Sun; Naseem Zojwalla; Tai Wong; James P Rizzi; Eli M Wallace; John A Josey; Yang Xie; Xian-Jin Xie; Payal Kapur; Renée M McKay; James Brugarolas Journal: Nature Date: 2016-09-05 Impact factor: 49.962
Authors: Lauren E Colbert; Sarah B Fisher; Serdar Balci; Burcu Saka; Zhengjia Chen; Sungjin Kim; Bassel F El-Rayes; N Volkan Adsay; Shishir K Maithel; Jerome C Landry; Walter J Curran Journal: Int J Radiat Oncol Biol Phys Date: 2015-01-13 Impact factor: 7.038
Authors: Eric Jonasch; Frede Donskov; Othon Iliopoulos; W Kimryn Rathmell; Vivek K Narayan; Benjamin L Maughan; Stephane Oudard; Tobias Else; Jodi K Maranchie; Sarah J Welsh; Sanjay Thamake; Eric K Park; Rodolfo F Perini; W Marston Linehan; Ramaprasad Srinivasan Journal: N Engl J Med Date: 2021-11-25 Impact factor: 176.079
Authors: Cullen M Taniguchi; Yu Rebecca Miao; Anh N Diep; Colleen Wu; Erinn B Rankin; Todd F Atwood; Lei Xing; Amato J Giaccia Journal: Sci Transl Med Date: 2014-05-14 Impact factor: 17.956
Authors: Surendra K Shukla; Vinee Purohit; Kamiya Mehla; Venugopal Gunda; Nina V Chaika; Enza Vernucci; Ryan J King; Jaime Abrego; Gennifer D Goode; Aneesha Dasgupta; Alysha L Illies; Teklab Gebregiworgis; Bingbing Dai; Jithesh J Augustine; Divya Murthy; Kuldeep S Attri; Oksana Mashadova; Paul M Grandgenett; Robert Powers; Quan P Ly; Audrey J Lazenby; Jean L Grem; Fang Yu; José M Matés; John M Asara; Jung-Whan Kim; Jordan H Hankins; Colin Weekes; Michael A Hollingsworth; Natalie J Serkova; Aaron R Sasson; Jason B Fleming; Jennifer M Oliveto; Costas A Lyssiotis; Lewis C Cantley; Lyudmyla Berim; Pankaj K Singh Journal: Cancer Cell Date: 2017-07-10 Impact factor: 38.585
Authors: James A McCubrey; Li V Yang; Stephen L Abrams; Linda S Steelman; Matilde Y Follo; Lucio Cocco; Stefano Ratti; Alberto M Martelli; Giuseppa Augello; Melchiorre Cervello Journal: Cells Date: 2022-07-09 Impact factor: 7.666