Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival |
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| Affiliation: | 1. Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;3. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;4. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;5. Evolution of Cancer, Leukemia and Immunity Post Stem Cell Transplant (ECLIPSE), The University of Texas MD Anderson Cancer Center, Houston, TX, USA;1. Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, United States;2. Division of Gastroenterology and Hepatology, John H. Stroger Cook County Hospital, Chicago, IL, United States;3. Department of Gastroenterology, BIDMC, Boston, United States;4. Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, United States;5. Division of Gastroenterology and Hepatology, Fox Chase Cancer Center, Philadelphia, United States;6. Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, United States;1. Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany;2. Department of Neuroradiology, University Medical Center Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany;3. Department of Radiology, University Medical Center Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany;4. Department of General Surgery, Bogomolets National Medical Unoversity, Kiev, Ukraine;1. Department of Anatomy and Cell Biology, Iowa City, IA, USA;2. Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA;3. Department of Pediatrics, lowa City, IA, USA;4. Department of Biochemistry, Iowa City, IA, USA;5. Department of Radiation Oncology; University of Iowa, Iowa City, IA, USA;6. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA;1. Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa, Japan;2. Department of Cardiovascular Surgery, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa, Japan;3. Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, 3-1, North-33, East-14, Higashi-Ku, Sapporo, Japan;1. Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic;2. Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA;3. Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA;4. Clinic of Internal Medicine, University Hospital Ostrava, Ostrava, Czech Republic;5. Gastroenterology Unit, Pancreas Center, University of Verona, Verona, Italy;6. Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan;7. Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan;8. Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan;9. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;10. Department of Gastroenterology, San Carlo Hospital, Potenza, Italy;11. Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden;12. Department for Upper Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden;13. CLINTEC, Karolinska Institute, Stockholm, Sweden;14. Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden |
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| Abstract: | BackgroundCD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear.MethodsThis study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4+, CD8+, CD21+ and CD45RO + tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs.ResultsCD73 overexpression correlated with poor differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.02) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4+ TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort.ConclusionsCD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4+, CD8+ and CD21+ TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC. |
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| Keywords: | Pancreatic cancer CD73 Adenosine Prognosis Immunotherapy Tumor microenvironment Tumor infiltrating lymphocytes |
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