Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target
Related Experiment Video
Updated: Nov 23, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Xiuning Le1, Marcelo V Negrao1, Alexandre Reuben1
1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
EGFR-mutant lung cancer shows an immune-inert phenotype, resisting current therapies. Targeting the CD73/adenosine pathway offers a promising new strategy to improve treatment response in these patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung adenocarcinomas with EGFR mutations are resistant to immune checkpoint blockade therapy.
- The underlying mechanisms for this resistance are not fully understood.
Purpose of the Study:
- To investigate the tumor immune microenvironment in EGFR-mutant lung adenocarcinomas.
- To identify potential therapeutic targets to enhance treatment response.
Main Methods:
- Analysis of three lung adenocarcinoma cohorts (PRoSPECT, IGPP, TCGA).
- Comparison of immune microenvironment between EGFR-mutant and wildtype tumors.
- Single-cell analysis and in vivo mouse models.
Main Results:
- EGFR-mutant NSCLC exhibits an immune-inert phenotype (low PD-L1, low TMB, fewer cytotoxic T cells).
- The CD73/adenosine pathway (NT5E, ADORA1) is upregulated in EGFR-mutant tumors.
- CD73 blockade inhibited tumor growth in a mouse model.
Conclusions:
- EGFR-mutant lung cancer presents an immune-inert phenotype.
- The CD73/adenosine pathway is a potential therapeutic target for EGFR-mutant NSCLC.
