CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer-Reference-Cited by-同舟云学术

CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Published:2023-01-31 Issue:7 Volume:83 Page:1111-1127
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Faraoni Erika Y.¹^ORCID,Singh Kanchan¹^ORCID,Chandra Vidhi²³^ORCID,Le Roux Olivereen²^ORCID,Dai Yulin⁴^ORCID,Sahin Ismet⁵^ORCID,O'Brien Baylee J.¹^ORCID,Strickland Lincoln N.¹^ORCID,Li Le²^ORCID,Vucic Emily⁶^ORCID,Warner Amanda N.¹³^ORCID,Pruski Melissa⁷^ORCID,Clark Trent¹^ORCID,Van Buren George⁸^ORCID,Thosani Nirav C.⁷⁹^ORCID,Bynon John S.¹⁰^ORCID,Wray Curtis J.¹⁰^ORCID,Bar-Sagi Dafna⁵^ORCID,Poulsen Kyle L.¹¹¹^ORCID,Vornik Lana A.²^ORCID,Savage Michelle I.²^ORCID,Sei Shizuko¹²^ORCID,Mohammed Altaf¹²^ORCID,Zhao Zhongming⁴^ORCID,Brown Powel H.²^ORCID,Mills Tingting¹³^ORCID,Eltzschig Holger K.¹¹¹^ORCID,McAllister Florencia²³¹⁴¹⁵^ORCID,Bailey-Lundberg Jennifer M.¹³⁷⁹¹¹^ORCID

Affiliation:

1. 1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

2. 2Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

3. 3The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, and The University of Texas Health Science Center at Houston, Houston, Texas.

4. 4Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.

5. 5Department of Engineering, Texas Southern University, Houston, Texas.

6. 6Departments of Biochemistry and Molecular Pharmacology and Medicine, NYU Langone School of Medicine, New York, New York.

7. 7Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

8. 8Division of Surgical Oncology, Baylor College of Medicine, Houston, Texas.

9. 9Center for Interventional Gastroenterology at UTHealth (iGUT), McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

10. 10Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

11. 11Center for Perioperative Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

12. 12Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.

13. 13Department of Biochemistry, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

14. 14Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

15. 15Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

AbstractThe microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin–dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention.Significance:Ductal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell–mediated tumor regression.See related commentary by DelGiorno, p. 977

Funder

V Foundation for Cancer Research

National Institutes of Health

Cancer Prevention and Research Institute of Texas

Division of Cancer Prevention, National Cancer Institute

American Association for Cancer Research

Office of Extramural Research, National Institutes of Health

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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