PMID- 33158943 OWN - NLM STAT- MEDLINE DCOM- 20210208 LR - 20231213 IS - 1521-0103 (Electronic) IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 376 IP - 1 DP - 2021 Jan TI - Downregulation of Interferon-gamma Receptor Expression Endows Resistance to Anti-Programmed Death Protein 1 Therapy in Colorectal Cancer. PG - 21-28 LID - 10.1124/jpet.120.000284 [doi] AB - 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-gamma pathway could result in acquired resistance to immune checkpoint inhibitors in human patients with cancer. Here, we investigated the effects of the IFN-gamma receptor downexpression on the response to an anti-PD-1 antibody (alphaPD1) in a murine colorectal cancer model and the underlying mechanisms of resistance. IFN-gamma 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 alphaPD1 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 alphaPD1 did not impact this pattern of spatial distribution. Our findings have proved that downregulation of the IFNGR1 endowed resistance to alphaPD1 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-gamma 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. CI - Copyright (c) 2020 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Lv, Chunxiao AU - Lv C AD - 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. FAU - Yuan, Dongfen AU - Yuan D AD - 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. FAU - Cao, Yanguang AU - Cao Y AD - 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 yanguang@unc.edu. LA - eng GR - R35 GM119661/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20201106 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Receptors, Interferon) SB - IM MH - Adenocarcinoma/drug therapy/*genetics MH - Animals MH - Cell Line, Tumor MH - Colorectal Neoplasms/drug therapy/*genetics MH - Down-Regulation MH - *Drug Resistance, Neoplasm MH - Female MH - Immune Checkpoint Inhibitors/pharmacology/therapeutic use MH - Mice MH - Mice, Inbred C57BL MH - Programmed Cell Death 1 Receptor/*antagonists & inhibitors MH - Receptors, Interferon/*genetics/metabolism MH - Interferon gamma Receptor PMC - PMC7745088 COIS- No author has an actual or perceived conflict of interest with the contents of this article. EDAT- 2020/11/08 06:00 MHDA- 2021/02/09 06:00 PMCR- 2022/01/01 CRDT- 2020/11/07 05:28 PHST- 2020/08/13 00:00 [received] PHST- 2020/10/26 00:00 [accepted] PHST- 2020/11/08 06:00 [pubmed] PHST- 2021/02/09 06:00 [medline] PHST- 2020/11/07 05:28 [entrez] PHST- 2022/01/01 00:00 [pmc-release] AID - jpet.120.000284 [pii] AID - JPET_AR2020000284 [pii] AID - 10.1124/jpet.120.000284 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2021 Jan;376(1):21-28. doi: 10.1124/jpet.120.000284. Epub 2020 Nov 6.