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Cancer Immunology Research
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Research Articles

IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer

Bhalchandra Mirlekar, Daniel Michaud, Ryan Searcy, Kevin Greene and Yuliya Pylayeva-Gupta
Bhalchandra Mirlekar
1Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
2The Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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Daniel Michaud
2The Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
3Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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Ryan Searcy
1Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
2The Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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Kevin Greene
2The Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
4Department of Pathology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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Yuliya Pylayeva-Gupta
1Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
2The Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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  • For correspondence: yuliyap1@email.unc.edu
DOI: 10.1158/2326-6066.CIR-17-0710 Published September 2018
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Abstract

Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced. An analysis of tumor-infiltrating immune cells revealed a role for IL35 in the expansion of regulatory T cells and the suppression of CD4+ effector T cells. We also detected a robust increase in both the infiltration and activation of cytotoxic CD8+ T cells, suggesting that targeting IL35 may be an effective strategy to convert PDA from an immunologically “cold” to “hot” tumor. Although PDA is typically resistant to anti–PD-1 immunotherapy, we demonstrated robust synergistic reduction in tumor growth when IL35 deficiency was combined with anti–PD-1 treatment. These findings provide new insight into the function of IL35 in the pathogenesis of pancreatic cancer and underscore the potential significance of IL35 as a therapeutic target for use in combination immunotherapy approaches in this deadly malignancy. Cancer Immunol Res; 6(9); 1014–24. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received December 6, 2017.
  • Revision received April 24, 2018.
  • Accepted June 25, 2018.
  • Published first July 6, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Immunology Research: 6 (9)
September 2018
Volume 6, Issue 9
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IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer
Bhalchandra Mirlekar, Daniel Michaud, Ryan Searcy, Kevin Greene and Yuliya Pylayeva-Gupta
Cancer Immunol Res September 1 2018 (6) (9) 1014-1024; DOI: 10.1158/2326-6066.CIR-17-0710

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IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer
Bhalchandra Mirlekar, Daniel Michaud, Ryan Searcy, Kevin Greene and Yuliya Pylayeva-Gupta
Cancer Immunol Res September 1 2018 (6) (9) 1014-1024; DOI: 10.1158/2326-6066.CIR-17-0710
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