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Cancer Immunology Research
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Research Article

IRF1 inhibits antitumor immunity through the upregulation of PD-L1 in the tumor cell

Lulu Shao, Weizhou Hou, Nicole E Scharping, Frank P Vendetti, Rashmi Srivastava, Chandra Nath Roy, Ashley V Menk, Yiyang Wang, Joe-Marc Chauvin, Pooja Karukonda, Steve H. Thorne, Veit Hornung, Hassane M. Zarour, Christopher J Bakkenist, Greg M. Delgoffe and Saumendra N Sarkar
Lulu Shao
1Microbiology and Molecular Genetics, University of Pittsburgh
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Weizhou Hou
2University of Pittsburgh Cancer Institute, University of Pittsburgh
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Nicole E Scharping
3Immunology, University of Pittsburgh
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Frank P Vendetti
4Radiation Oncology, University of Pittsburgh School of Medicine
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Rashmi Srivastava
1Microbiology and Molecular Genetics, University of Pittsburgh
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Chandra Nath Roy
2University of Pittsburgh Cancer Institute, University of Pittsburgh
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Ashley V Menk
5University of Pittsburgh Cancer Institute
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Yiyang Wang
3Immunology, University of Pittsburgh
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Joe-Marc Chauvin
6Medicine, University of Pittsburgh
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Pooja Karukonda
2University of Pittsburgh Cancer Institute, University of Pittsburgh
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Steve H. Thorne
3Immunology, University of Pittsburgh
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Veit Hornung
7Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München
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Hassane M. Zarour
8Medicine and Immunology, University of Pittsburgh
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Christopher J Bakkenist
9Radiation Oncology, University of Pittsburgh
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Greg M. Delgoffe
3Immunology, University of Pittsburgh
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Saumendra N Sarkar
2University of Pittsburgh Cancer Institute, University of Pittsburgh
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  • For correspondence: saumen@pitt.edu
DOI: 10.1158/2326-6066.CIR-18-0711
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Abstract

Multiple studies have associated the transcription factor IRF1 with tumor suppressive activities. Here we report an opposite tumor cell-intrinsic function of IRF1 in promoting tumor growth. IRF1-deficient tumor cells showed reduced tumor growth in MC38 and CT26 colon carcinoma and B16 melanoma mouse models. This reduction in tumor growth was dependent on host CD8+ T cells. Detailed profiling of tumor-infiltrating leukocytes did not show changes in the various T cell and myeloid cell populations. However, CD8+ T cells that had infiltrated IRF1-deficieint tumors in vivo exhibited enhanced cytotoxicity. IRF1-deficient tumor cells lost the ability to upregulate PD-L1 expression in vitro and in vivo and were more susceptible to T cell-mediated killing. Induced expression of PD-L1 in IRF1-deficient tumor cells restored tumor growth. These results indicate differential activity of IRF1 in tumor escape.

  • Received October 4, 2018.
  • Revision received March 29, 2019.
  • Accepted June 19, 2019.
  • Copyright ©2019, American Association for Cancer Research.
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This OnlineFirst version was published on June 25, 2019
doi: 10.1158/2326-6066.CIR-18-0711

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IRF1 inhibits antitumor immunity through the upregulation of PD-L1 in the tumor cell
Lulu Shao, Weizhou Hou, Nicole E Scharping, Frank P Vendetti, Rashmi Srivastava, Chandra Nath Roy, Ashley V Menk, Yiyang Wang, Joe-Marc Chauvin, Pooja Karukonda, Steve H. Thorne, Veit Hornung, Hassane M. Zarour, Christopher J Bakkenist, Greg M. Delgoffe and Saumendra N Sarkar
Cancer Immunol Res June 25 2019 DOI: 10.1158/2326-6066.CIR-18-0711

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IRF1 inhibits antitumor immunity through the upregulation of PD-L1 in the tumor cell
Lulu Shao, Weizhou Hou, Nicole E Scharping, Frank P Vendetti, Rashmi Srivastava, Chandra Nath Roy, Ashley V Menk, Yiyang Wang, Joe-Marc Chauvin, Pooja Karukonda, Steve H. Thorne, Veit Hornung, Hassane M. Zarour, Christopher J Bakkenist, Greg M. Delgoffe and Saumendra N Sarkar
Cancer Immunol Res June 25 2019 DOI: 10.1158/2326-6066.CIR-18-0711
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