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

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 IFNgamma signature that was absent in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNgamma and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of Socs1, an inhibitor of IFNgamma. Silencing Socs1 increased response to IFNgamma 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 IFNgamma signaling can induce of cascade of changes associated with increased therapeutic vulnerability.