A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Common epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are generally unresponsive to immunotherapy.
• The immunotherapeutic potential of uncommon EGFR mutations remains largely unexplored.

Purpose of the Study:

• To investigate the tumor immune microenvironment (TME) characteristics associated with uncommon EGFR mutations in NSCLC.
• To compare the TME of uncommon EGFR mutant NSCLC with common EGFR mutant NSCLC.

Main Methods:

• Multi-institutional study including 41 patients with EGFR mutations (22 common, 19 uncommon), predominantly Stage I.
• Multiplex immunofluorescence (mIF) profiling to analyze TME features.
• Unsupervised clustering to identify distinct TME subclasses within uncommon EGFR mutations.
• Validation in The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort.

Main Results:

• Uncommon EGFR mutations exhibited increased T cell infiltration and decreased M2 macrophage presence compared to common mutations.
• Upregulated antigen processing and presentation pathways were observed in uncommon EGFR mutant tumors.
• Two distinct TME clusters were identified in uncommon EGFR mutations: one lacking cytotoxic T cells, the other 'hotter' with downregulated hypoxia, oxidative phosphorylation, and TGF-beta signaling, and upregulated CTLA4 and PDCD1.
• CTLA4 and PDCD1 associations with TME profiles were validated in a TCGA cohort.

Conclusions:

• Uncommon EGFR mutations are associated with a distinct TME profile in NSCLC, differing significantly from common mutations.
• Heterogeneity exists within the TME of uncommon EGFR mutant NSCLC, with potential implications for immunotherapy response.
• Further research into immunotherapy strategies targeting uncommon EGFR mutations is warranted based on these TME findings.