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Tumor-intrinsic response to IFN? 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-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 IFN? signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFN? and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFN?. Silencing Socs1 increased response to IFN? 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 IFN? signaling can induce a cascade of changes associated with increased therapeutic vulnerability.

SUBMITTER: Bullock BL

PROVIDER: S-EPMC6537751 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC.

Bullock Bonnie L BL Kimball Abigail K AK Poczobutt Joanna M JM Neuwelt Alexander J AJ Li Howard Y HY Johnson Amber M AM Kwak Jeff W JW Kleczko Emily K EK Kaspar Rachael E RE Wagner Emily K EK Hopp Katharina K Schenk Erin L EL Weiser-Evans Mary Cm MC Clambey Eric T ET Nemenoff Raphael A RA

Life science alliance 20190527 3

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 ce ...[more]

PMID: 31133614

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Project description:PurposeImmunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization.Experimental designPatients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes.ResultsMembranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response.ConclusionsTumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ©2014 AACR.

Dataset Information

Tumor-intrinsic response to IFN? shapes the tumor microenvironment and anti-PD-1 response in NSCLC.

Publications

Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC.

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