Xiuning Le1, Marcelo V Negrao1, Alexandre Reuben1, Lorenzo Federico2, Lixia Diao3, Daniel McGrail4, Monique Nilsson1, Jacqulyne Robichaux1, Irene Guijarro Munoz1, Sonia Patel1, Yasir Elamin1, You-Hong Fan1, Won-Chul Lee1, Edwin Parra5, Luisa Maren Solis Soto5, Runzhe Chen1, Jun Li6, Tatiana Karpinets6, Roohussaba Khairullah1, Humam Kadara5, Carmen Behrens5, Boris Sepesi7, Ruiping Wang6, Mingrui Zhu8, Linghua Wang6, Ara Vaporciyan7, Jack Roth7, Stephen Swisher7, Cara Haymaker5, Jianhua Zhang6, Jing Wang2, Kwok-Kin Wong9, Lauren A Byers1, Chantale Bernatchez10, Jianjun Zhang11, Ignacio I Wistuba5, Don L Gibbons1, Esra A Akbay12, John V Heymach13. 1. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Department of Bioinformatics and Computational Biology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4. Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. 8. Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas. 9. Division of Hematology and Medical Oncology, NYU Perlmutter Cancer Center, New York, New York; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 10. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 11. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 12. Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 13. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: jheymach@mdanderson.org.
Abstract
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.
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.
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Authors: Eric Tu; Kelly McGlinchey; Jixin Wang; Philip Martin; Steven Lk Ching; Nicolas Floc'h; James Kurasawa; Jacqueline H Starrett; Yelena Lazdun; Leslie Wetzel; Barrett Nuttall; Felicia Sl Ng; Karen T Coffman; Paul D Smith; Katerina Politi; Zachary A Cooper; Katie Streicher Journal: JCI Insight Date: 2022-02-08