Immune profiles according to EGFR mutant subtypes and correlation with PD-1/PD-L1 inhibitor therapies in lung adenocarcinoma

BACKGROUND: We examined the distributions of 22 immune cell types and the responses to PD-1/PD-L1 inhibitors according to EGFR mutation profile, in three independent datasets of lung adenocarcinoma (LUAD). METHODS: We used CIBERSORTx to analyze the distributions of immune cells, and tumor immune dysfunction and exclusion (TIDE) or tumor mutation burden (TMB) to analyze responses to anti-PD-1/PD-L1 therapy, in two public LUAD datasets. The results were verified with a validation set that included patients treated with PD-1/PD-L1 inhibitors. RESULTS: Compared to EGFR mutants, EGFR wild-type carcinomas had higher numbers of CD8+ T cells, CD4 memory activated T cells and neutrophils, and lower numbers of resting dendritic cells and resting mast cells, in two of the datasets. In our subgroup analyses, CD8+ T cells and CD4 memory activated T cells were more numerous in EGFR rare variants than in wild-types, L858R mutants, and exon 19 deletion mutants. In our TIDE or TMB analyses, EGFR rare variants were predicted to respond better to PD-1/PD-L1 inhibitors than wild-types, L858R mutants, and exon 19 deletion mutants. In the validation set verified by immunohistochemical staining, levels of CD8+ T cells in the EGFR rare variant or wild-type groups were significantly higher than in the EGFR L858R and exon 19 deletion groups. In patients treated with PD-1/PD-L1 inhibitors, the survival rates of patients with EGFR wild-type and rare mutant carcinomas were higher than those with L858R and exon 19 deletion carcinomas. CONCLUSION: The EGFR rare mutation form of LUAD shows a higher immune activation state compared to wild-type, L858R, and exon 19 deletion variants, indicating it as a potential target for PD-1/PD-L1 inhibitor therapy.