Characterization of the immune landscape of EGFR-mutant NSCLC identifies CD73/adenosine pathway as a potential therapeutic target.

ABSTRACT Introduction Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy as well as 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 (PROSPECT, ICON and TCGA) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR-wildtype (WT) tumors, to identify actionable regulators to target and potentially enhance the treatment response. Results EGFR-mutant NSCLC exhibited low PD-L1, 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 demonstrated that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using co-culture 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 upregulated and CD73 blockade significantly inhibited tumor growth. Conclusions Our work demonstrated that EGFR-mutant NSLCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.