Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC
Bullock, B.L., Kimball, A.K., Poczobutt, J.M. et al.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–mutant lung cancer cell lines to anti–PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti–PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti–PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.
Bullock, B.L., Kimball, A.K., Poczobutt, J.M. et al. "Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC" Life Science Alliance (2019): e201900328