@article{f025f5c44ec24020b889663e6a0c9dbc,
title = "STING Pathway Expression Identifies NSCLC With an Immune-Responsive Phenotype",
abstract = "Introduction: Although the combination of anti–programmed cell death-1 or anti–programmed cell death ligand-1 (PD-L1) with platinum chemotherapy is a standard of care for NSCLC, clinical responses vary. Even though predictive biomarkers (which include PD-L1 expression, tumor mutational burden, and inflamed immune microenvironment) are validated for immunotherapy, their relevance to chemoimmunotherapy combinations is less clear. We have recently reported that activation of the stimulator of interferon genes (STING) innate immune pathway enhances immunotherapy response in SCLC. Here, we hypothesize that STING pathway activation may predict and underlie predictive correlates of antitumor immunity in NSCLC. Methods: We analyzed transcriptomic and proteomic profiles in two NSCLC cohorts from our institution (treatment-naive patients in the Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax study and relapsed patients in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination study) and The Cancer Genome Atlas (N = 1320). Tumors were stratified by STING activation on the basis of protein or mRNA expression of cyclic GMP-AMP synthase, phospho-STING, and STING-mediated chemokines (chemokine ligand 5 [CCL5] and C-X-C motif chemokine 10 [CXCL10]). STING activation in patient tumors and in platinum-treated preclinical NSCLC models was correlated with biomarkers of immunotherapy response. Results: STING activation is associated with higher levels of intrinsic DNA damage, targetable immune checkpoints, and chemokines in treatment-naive and relapsed lung adenocarcinoma. We observed that tumors with lower STING and immune gene expression show higher frequency of serine-threonine kinase 11 (STK11) mutations; however, we identified a subset of these tumors that are TP53 comutated and display high immune- and STING-related gene expression. Treatment with cisplatin increases STING pathway activation and PD-L1 expression in multiple NSCLC preclinical models, including adeno- and squamous cell carcinoma. Conclusions: STING pathway activation in NSCLC predicts features of immunotherapy response and is enhanced by cisplatin treatment. This suggests a possible predictive biomarker and mechanism for improved response to chemoimmunotherapy combinations.",
keywords = "Immune checkpoints, Immunotherapy, Innate immunity, Lung cancer, STING",
author = "{Della Corte}, {Carminia M.} and Triparna Sen and Gay, {Carl M.} and Kavya Ramkumar and Lixia Diao and Cardnell, {Robert J.} and Rodriguez, {Bertha Leticia} and Stewart, {C. Allison} and Papadimitrakopoulou, {Vassiliki A.} and Laura Gibson and Fradette, {Jared J.} and Qi Wang and Youhong Fan and Peng, {David H.} and Negrao, {Marcelo V.} and Wistuba, {Ignacio I.} and Junya Fujimoto and {Solis Soto}, {Luisa M.} and Carmen Behrens and Ferdinandos Skoulidis and Heymach, {John V.} and Jing Wang and Gibbons, {Don L.} and Byers, {Lauren A.}",
note = "Funding Information: This work was supported by the following: (1) the National Institutes of Health / National Cancer Institute (NIH/NCI) Cancer Center Support Grants P30-CA016672 (Bioinformatics Shared Resource); (2) Lung Cancer Research Foundation (Dr. Sen); (3) NIH / NCI T32 CA009666 (Dr. Gay); (4) ASCO Young Investigator Award (Dr. Gay); (5) institutional research support from Eli Lilly , Novartis , Merck , Nektar, Astra Zeneca , F. Hoffman-La Roche , Janssen, Checkmate, Incyte, and Bristol-Myers Squibb (Dr. Papadimitrakopoulou); (6) the University of Texas -Southwestern and MD Anderson Cancer Center Lung SPORE ( 5 P50 CA070907 ); (7) NCI R37 CA21460 (Dr. Gibbons); (8) NIH / NCI R01-CA207295 (Dr. Byers); (9) NIH / NCI R01-CA205150 (Dr. Heymach); (10) NIH / NCI U01-CA213273 (Drs. Byers and Heymach); (11) research support from AstraZeneca , Bayer , GlaxoSmithKline , Spectrum (Dr. Heymach); (12) the Department of Defense LC170171 (Dr. Byers); (13) philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (Drs. Heymach, Wang, Byers, and Gibbons); (13) CPRIT - MIRA RP160652 (Drs. Heymach and Gibbons); (14) the MD Anderson Cancer Center SCLC Working Group and Abell Hangar Foundation Distinguished Professor Endowment (Dr. Byers); (15) MD Anderson Cancer Center Physician Scientist Award (Drs. Byers and Gibbons); (16) the Rexanna Foundation for Fighting Lung Cancer (Drs. Heymach, Byers, and Gibbons); and (17) Sabin fellowship (Dr. Byers). The authors also thank the members of Translational Molecular Pathology Immunoprofiling Laboratory Wei Lu, Mei Jiang, Jianling Zhou, Jocelyn Coronel, and Lakshmi Kakarala for their technical expertise provided on histologic processing and immunohistochemical staining. Funding Information: Disclosure: Dr. Papadimitrakopoulou has served on advisory boards for Nektar Therapeutics, Bristol-Myers Squibb, Astra Zeneca, Novartis, Merck, Arrys Therapeutics, Zara Ed Pharma, Loxo Oncology, Inc., F. Hoffman-La Roche, Janssen Research Foundation, Clovis Oncology, Eli Lilly, Takeda, AbbVie, Tesaro, Exelixis, and Gritstone Oncology; has received speaker fees from F. Hoffman-La Roche; and is currently affiliated with Pfizer. Dr. Witsuba serves on advisory boards for Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, and MSD; has received speaker fees from Medscape, MSD, Genentech/Roche, and Pfizer; and has received research funding from Genentech, Oncoplex, HTG Molecular, DEPArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson and Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. Dr. Skoulidis received honoraria from Bristol-Myers Squibb. Dr. Heymach serves on advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GSK, Guardant Health, Hengrui, Lilly, Novartis, Spectrum, EMD Serono, and Synta. Dr. Gibbons serves on advisory committees for AstraZeneca, GlaxoSmithKline, Sanofi, Ribon Therapeutics, Alethia Biotherapeutics, Inc., and Janssen, and receives research funding from AstraZeneca, Janssen Research and Development, Takeda, and Ribon Therapeutics. Dr. Byers provides consultation for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar, Sanofi Aventis, Sierra Oncology, Bristol-Myers Squibb, and Alethia Biotherapeutics, Inc., and receives research funding from AstraZeneca, AbbVie, GenMab, and Sierra Oncology. The rest of the authors declare no conflict of interest.This work was supported by the following: (1) the National Institutes of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grants P30-CA016672 (Bioinformatics Shared Resource); (2) Lung Cancer Research Foundation (Dr. Sen); (3) NIH/NCI T32 CA009666 (Dr. Gay); (4) ASCO Young Investigator Award (Dr. Gay); (5) institutional research support from Eli Lilly, Novartis, Merck, Nektar, Astra Zeneca, F. Hoffman-La Roche, Janssen, Checkmate, Incyte, and Bristol-Myers Squibb (Dr. Papadimitrakopoulou); (6) the University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE (5 P50 CA070907); (7) NCI R37 CA21460 (Dr. Gibbons); (8) NIH/NCI R01-CA207295 (Dr. Byers); (9) NIH/NCI R01-CA205150 (Dr. Heymach); (10) NIH/NCI U01-CA213273 (Drs. Byers and Heymach); (11) research support from AstraZeneca, Bayer, GlaxoSmithKline, Spectrum (Dr. Heymach); (12) the Department of Defense LC170171 (Dr. Byers); (13) philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (Drs. Heymach, Wang, Byers, and Gibbons); (13) CPRIT-MIRA RP160652 (Drs. Heymach and Gibbons); (14) the MD Anderson Cancer Center SCLC Working Group and Abell Hangar Foundation Distinguished Professor Endowment (Dr. Byers); (15) MD Anderson Cancer Center Physician Scientist Award (Drs. Byers and Gibbons); (16) the Rexanna Foundation for Fighting Lung Cancer (Drs. Heymach, Byers, and Gibbons); and (17) Sabin fellowship (Dr. Byers). The authors also thank the members of Translational Molecular Pathology Immunoprofiling Laboratory Wei Lu, Mei Jiang, Jianling Zhou, Jocelyn Coronel, and Lakshmi Kakarala for their technical expertise provided on histologic processing and immunohistochemical staining. Publisher Copyright: {\textcopyright} 2020 International Association for the Study of Lung Cancer",
year = "2020",
month = may,
doi = "10.1016/j.jtho.2020.01.009",
language = "English (US)",
volume = "15",
pages = "777--791",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "5",
}