Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target

Xiuning Le, Marcelo V. Negrao, Alexandre Reuben, Lorenzo Federico, Lixia Diao, Daniel McGrail, Monique Nilsson, Jacqulyne Robichaux, Irene Guijarro Munoz, Sonia Patel, Yasir Elamin, You Hong Fan, Won Chul Lee, Edwin Parra, Luisa Maren Solis Soto, Runzhe Chen, Jun Li, Tatiana Karpinets, Roohussaba Khairullah, Humam KadaraCarmen Behrens, Boris Sepesi, Ruiping Wang, Mingrui Zhu, Linghua Wang, Ara Vaporciyan, Jack Roth, Stephen Swisher, Cara Haymaker, Jianhua Zhang, Jing Wang, Kwok Kin Wong, Lauren A. Byers, Chantale Bernatchez, Jianjun Zhang, Ignacio I. Wistuba, Don L. Gibbons, Esra A. Akbay, John V. Heymach

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)583-600
Number of pages18
JournalJournal of Thoracic Oncology
Volume16
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Adenosine
  • CD73
  • EGFR-mutant lung cancer
  • Immune microenvironment
  • T cells

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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