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      JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer

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          ABSTRACT

          Human pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration. JAK-STAT inhibitor Ruxolitinib selectively inhibits STAT1 and STAT3 activation and increases CTL infiltration to induce a Tc1/Th1 immune response in the tumor microenvironment in an orthotopic pancreatic cancer mouse model. Ruxilitinib-mediated tumor suppressive efficacy diminishes in T-cell-deficient mice. Pancreatic tumor grows significantly faster in IFNγ-deficient mice. However, neutralizing IFNγ does not alter tumor growth but diminishes Ruxolitinib-induced tumor suppression in vivo, indicating that lymphocytes and IFNγ are essential for Ruxolitinib-induced host antitumor immune response. Both type I and type II interferons upregulate PD-L1 expression through the JAK-STAT signaling pathway in mouse pancreatic tumor cells. Tumor cells respond to activated T cells by activating STAT3. The inhibition of STAT3 downregulates immune suppressive cytokines production by tumor cells, resulting in increased T cell activation and effector function. Consequently, Ruxolitinib significantly improves the efficacy of anti-PD-1 immunotherapy. Our data demonstrate that Ruxolitinib is effective in the inhibition of systemic inflammation in the tumor microenvironment and therefore upregulates CTL infiltration and activation to overcome pancreatic cancer resistance to anti-PD-1 immunotherapy.

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          Author and article information

          Journal
          Oncoimmunology
          Oncoimmunology
          KONI
          koni20
          Oncoimmunology
          Taylor & Francis
          2162-4011
          2162-402X
          2017
          10 February 2017
          : 6
          : 3
          Affiliations
          [a ] Department of Biochemistry and Molecular Biology, Medical College of Georgia , Augusta, GA, USA
          [b ] Georgia Cancer Center , Augusta, GA, USA
          [c ] Charlie Norwood VA Medical Center , Augusta, GA, USA
          [d ] Department of Surgery, Pathology, Medical College of Georgia , Augusta, GA, USA
          [e ] Pathology, Medical College of Georgia , Augusta, GA, USA
          Author notes
          CONTACT Kebin Liu Kliu@ 123456augusta.edu Department of Biochemistry and Molecular Biology, Medical College of Georgia , Augusta, GA 30912, USA

          Supplemental data for this article can be accessed on the publisher's website.

          Article
          PMC5384417 PMC5384417 5384417 1291106
          10.1080/2162402X.2017.1291106
          5384417
          28405527
          © 2017 Taylor & Francis Group, LLC
          Page count
          Figures: 8, Tables: 0, Equations: 0, References: 70, Pages: 15
          Categories
          Original Research

          Ruxolitinib, STAT1, STAT3, Cytotoxic T Lymphocytes, FasL, PD-1, PD-L1

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