Down-regulation of the IFN-gamma receptor expression endows resistance to anti-PD-1 therapy in colorectal cancer

Colorectal Cancer
07/11/2020

J Pharmacol Exp Ther. 2020 Nov 6:JPET-AR-2020-000284. doi: 10.1124/jpet.120.000284. Online ahead of print.

ABSTRACT

Immune checkpoint inhibitors have emerged as a frontline treatment for 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 (PD-1) is one of the checkpoint inhibitors which expressed on activated T cells and suppresses the antitumor immune response when binds to its ligand PD-L1 on tumor cells. Previous studies indicated that loss-of-function


mutations in INF-γ pathway could result in acquired resistance to immune checkpoint inhibitors in human cancer patients. Here, we investigated the effects of the INF-γ receptor down-expression on the response to an anti-PD1 antibody (αPD1) in a murine colorectal cancer model and the underlying mechanisms of resistance. INF-γ receptor1 (IFN-γR1) was knocked down in MC38 cells (KD), a murine colon adenocarcinoma cell line using IFNGR1 shRNA lentiviral particles. Then, MC38 IFN-γR1 knockdown (KD) cells and negative control (SC) cells were used in this study. In C57BL/6 xenograft model, the KD tumor demonstrated resistance to αPD1 in comparison to 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 down-regulation of the IFN-γR1 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 down-regulation of the INF-γ receptor caused resistance to an anti-PD1 antibody (αPD1) 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.