Tumor-Intrinsic Response to IFNgamma Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

Abstract

Targeting PD-1/ PD-L1 is only effective in ~20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated while LLC tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA-Seq analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFN{gamma} signature that was absent in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFN{gamma} and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of Socs1, an inhibitor of IFN{gamma}. Silencing Socs1 increased response to IFN{gamma} in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped TME, characterized by enhanced T cell infiltration and enrichment of PD-L1 high myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFN{gamma} signaling can induce of cascade of changes associated with increased therapeutic vulnerability. SummaryMechanisms regulating response to anti-PD-1 therapy in lung cancer are not well defined. This study, using orthotopic immunocompetent mouse models of lung cancer, demonstrates that intrinsic sensitivity of cancer cells to IFN{gamma} determines anti-PD-1 responsiveness through alterations in the tumor microenvironment.