TY - JOUR
T1 - Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target
AU - Le, Xiuning
AU - Negrao, Marcelo V.
AU - Reuben, Alexandre
AU - Federico, Lorenzo
AU - Diao, Lixia
AU - McGrail, Daniel
AU - Nilsson, Monique
AU - Robichaux, Jacqulyne
AU - Munoz, Irene Guijarro
AU - Patel, Sonia
AU - Elamin, Yasir
AU - Fan, You Hong
AU - Lee, Won Chul
AU - Parra, Edwin
AU - Solis Soto, Luisa Maren
AU - Chen, Runzhe
AU - Li, Jun
AU - Karpinets, Tatiana
AU - Khairullah, Roohussaba
AU - Kadara, Humam
AU - Behrens, Carmen
AU - Sepesi, Boris
AU - Wang, Ruiping
AU - Zhu, Mingrui
AU - Wang, Linghua
AU - Vaporciyan, Ara
AU - Roth, Jack
AU - Swisher, Stephen
AU - Haymaker, Cara
AU - Zhang, Jianhua
AU - Wang, Jing
AU - Wong, Kwok Kin
AU - Byers, Lauren A.
AU - Bernatchez, Chantale
AU - Zhang, Jianjun
AU - Wistuba, Ignacio I.
AU - Gibbons, Don L.
AU - Akbay, Esra A.
AU - Heymach, John V.
N1 - Funding Information:
Disclosure: Dr. Le receives a consultant fee from Eli Lilly , AstraZeneca , EMD Serono , and Boehringer Ingelheim . Dr. Sepesi receives a consultant fee from Bristol-Myers Squibb . Robichaux has sponsored research agreement from Genprex, Inc ., has ownership interest (including stock, patents, etc.) in Genprex, Inc., and is a consultant/advisory board member for Genprex, Inc. Dr. Robichaux receives royalties and licensing fees from Spectrum. Dr. Nilsson receives licensing fees from Spectrum Pharmaceuticals and is an inventor on patents related to the treatment of EGFR mutant tumors. Dr. Zhang reports receiving research funding and personal fees from Bristol-Myers Squibb, AstraZeneca, Geneplus , OrigMed , and Innovent and grants from Merck and Johnson & Johnson outside of the current work. Dr. Behrens and Dr. Wistuba report receiving grants and personal fees from Genentech/Roche , Bayer , Bristol-Myers Squibb, AstraZeneca/Medimmune , Pfizer , HTG Molecular , Asuragen , Guardant Health , and Merck; personal fees from GlaxoSmithKline , Oncocyte , and Merck Sharp & Dohme ; and grants from Oncoplex , DepArray , Adaptive , Adaptimmune , EMD Serono , Takeda , Amgen , Karus , Johnson & Johnson, Iovance , 4D , Novartis , and Akoya outside of the submitted work. Dr. Kadara receives research funding from Johnson and Johnson and Janssen Pharmaceuticals. Dr. Haymaker serves on the scientific advisory board for Briacell . Dr. Wong is a founder and equity holder of G1 Therapeutics, has sponsored Research Agreements with Medimmune, Takeda, TargImmune , and Bristol-Myers Squibb, and has consulting and sponsored research agreements with AstraZeneca, Janssen , Pfizer, Novartis, Merck, Ono , and Array . Dr. Gibbons has served on scientific advisory committees for AstraZeneca, GlaxoSmithKline , Takeda, Sanofi , and Janssen and has received research support from Janssen Research and Development, Takeda, Ribon Therapeutics , Mitobridge , and AstraZeneca. Dr. Byers receives consultant and advisor fees from AstraZeneca, Abbvie, GenMab, PharmaMar, Sierra Oncology, Alethia, Merck, and Pfizer, and research funding from ToleroPharmaceuticals. Dr. Heymach has served on the scientific advisory boards for AstraZeneca, Biotree , Bristol-Myers Squibb, Boehringer Ingelheim, Catalyst, EMD Serono , Genentech , GlaxoSmithKline, Guardant Health , Hengrui , Eli Lilly, Novartis, Seattle Genetics , Spectrum , Synta , Foundation Medicine, Takeda, Mirati Therapeutics, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, and Leads Biolabs. He receives research support from AstraZeneca, Bayer, GlaxoSmithKline, Spectrum, and Takeda, and royalties and licensing fees from Spectrum. The remaining authors declare no conflict of interest.
Funding Information:
The authors acknowledge funding support from the University of Texas MD Anderson Lung Cancer Moon Shot Program and the MD Anderson Cancer Center Support grant P30 CA01667 , National Institutes of Health R01 CA190628 , UT Lung SPORE P50 CA70907 , Rexanna’s Foundation for Fighting Lung Cancer , Bruton Endowed Chair in Tumor Biology, the Hallman fund, and the Gil and Dody Weaver Foundation (to Dr. Heymach). Dr. Le is supported by the Paul Calabresi Clinical Oncology Award ( K-12 ) at MD Anderson Cancer Center, the Khalifa Scholars Award, and Conquer Cancer Foundation American Society of Clinical Oncology Career Development Award. Dr. Akbay is supported by the Cancer Prevention and Research Institute of Texas Scholar Award RR160080 , a Career Enhancement Award through the National Institutes of Health 5P50CA070907 , and Welch Foundation research grant ( 1975-20190330 ). Dr. Gibbons is supported by CPRIT grant RP200235 .
Publisher Copyright:
© 2021 International Association for the Study of Lung Cancer
PY - 2021/4
Y1 - 2021/4
N2 - Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
AB - Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
KW - Adenosine
KW - CD73
KW - EGFR-mutant lung cancer
KW - Immune microenvironment
KW - T cells
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U2 - 10.1016/j.jtho.2020.12.010
DO - 10.1016/j.jtho.2020.12.010
M3 - Article
C2 - 33388477
AN - SCOPUS:85102652007
VL - 16
SP - 583
EP - 600
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
SN - 1556-0864
IS - 4
ER -