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Research ArticleDrug Discovery and Translational Medicine

Downregulation of Interferon-γ Receptor Expression Endows Resistance to Anti–Programmed Death Protein 1 Therapy in Colorectal Cancer

Chunxiao Lv, Dongfen Yuan and Yanguang Cao
Journal of Pharmacology and Experimental Therapeutics January 2021, 376 (1) 21-28; DOI: https://doi.org/10.1124/jpet.120.000284
Chunxiao Lv
Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China (C.L.) and Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (C.L., D.Y., Y.C.) and Lineberger Comprehensive Cancer Center, School of Medicine (Y.C.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Dongfen Yuan
Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China (C.L.) and Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (C.L., D.Y., Y.C.) and Lineberger Comprehensive Cancer Center, School of Medicine (Y.C.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Yanguang Cao
Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China (C.L.) and Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (C.L., D.Y., Y.C.) and Lineberger Comprehensive Cancer Center, School of Medicine (Y.C.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Abstract

Immune checkpoint inhibitors have emerged as a frontline treatment of a variety of malignancies. However, only a subset of patients respond to these therapies, and many initial responders eventually develop resistance, leading to tumor relapse. Programmed death protein 1 is one of the checkpoint inhibitors that is expressed on activated T cells and suppresses the antitumor immune response when binding to its ligand, programmed death ligand 1, on tumor cells. Previous studies indicated that loss-of-function mutations in the IFN-γ pathway could result in acquired resistance to immune checkpoint inhibitors in human patients with cancer. Here, we investigated the effects of the IFN-γ receptor downexpression on the response to an anti–PD-1 antibody (αPD1) in a murine colorectal cancer model and the underlying mechanisms of resistance. IFN-γ receptor (IFNGR) 1 was knocked down in MC38 cells, a murine colon adenocarcinoma cell line using IFNGR1 short hairpin RNA (shRNA) lentiviral particles. Then, MC38 IFNGR1 knockdown (KD) cells and negative control (SC) cells were used in this study. In the C57BL/6 xenograft model, the KD tumor demonstrated resistance to αPD1 in comparison with SC cells. The observed treatment resistance might be associated with reduced tumor-infiltrating immune cells (TILs). When mixed, the resistant (KD) and control cells (SC) grew in spatially separated tumor areas, and αPD1 did not impact this pattern of spatial distribution. Our findings have proved that downregulation of the IFNGR1 endowed resistance to αPD1 and provided the potential mechanisms involving the TILs.

SIGNIFICANCE STATEMENT Immunological checkpoint blockades have achieved substantial efficacy in a variety of tumors. However, only a subset of patients respond to these therapies, and innate and acquired resistance is widely present. Our study found that the downregulation of the IFN-γ receptor caused resistance to an anti–PD-1 antibody in a murine colorectal cancer model associated with the reduced tumor-infiltrating lymphocytes. Our findings have substantial implications for improving the efficacy of checkpoint blockades.

Footnotes

    • Received August 13, 2020.
    • Accepted October 26, 2020.
  • ↵1 C.L. and D.Y. contributed equally to this work.

  • This work was supported by National Institutes of Health National Institute of General Medical Sciences [Grant R35 GM119661] to Y.C.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/jpet.120.000284.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 1
1 Jan 2021
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Research ArticleDrug Discovery and Translational Medicine

Downregulation of the IFN-γR Endows Resistance to αPD1

Chunxiao Lv, Dongfen Yuan and Yanguang Cao
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 21-28; DOI: https://doi.org/10.1124/jpet.120.000284

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Research ArticleDrug Discovery and Translational Medicine

Downregulation of the IFN-γR Endows Resistance to αPD1

Chunxiao Lv, Dongfen Yuan and Yanguang Cao
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 21-28; DOI: https://doi.org/10.1124/jpet.120.000284
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