Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC
Year: 2019
Type: article
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 IFNγ signature that was absent 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 TME, characterized by enhanced T cell infiltration and enrichment of PD-L1 high myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce of cascade of changes associated with increased therapeutic vulnerability. Summary Mechanisms 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 IFNγ determines anti-PD-1 responsiveness through alterations in the tumor microenvironment.
Source: Life Science Alliance
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: U.S. Department of Veterans Affairs, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Cancer Center, University of Colorado, Anschutz Medical Campus, University of Colorado, National Cancer Institute, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences
Awards: G1332742017, G1368206816, G1565180698, G2167001727, Eicosanoids in Lung Cancer: Progression and Metastasis, G2988872836, G3298087253, G3474153124, G3733990746, Effects of Complement on the Tumor Microenvironment in Lung Cancer, Predoctoral Training Grant in Pharmacology, Colorado Clinical and Translational Sciences Institute, G4543357668, G5029337574, Colorado Clinical and Translational Sciences Institute, G6241773839, G7135903733, G7405320585, SPORE in Lung Cancer, G8565077835, University of Colorado Cancer Center Support Grant
OpenAlex ID: W2914505559