Purpose: Although EGFR -mutated patients generally do not benefit from checkpoint inhibitors (ICIs), some patients in the KEYNOTE-001 study consistently benefited from this treatment. This study investigated immune microenvironment characteristics to identify the subgroup of patients that may benefit from ICIs. Materials and Methods: Using data from The Cancer Genome Atlas Program (TCGA) and Cancer Proteome Atlas, TMB and protein level of PD-L1 were explored in the patients with EGFR mutations and wild-type patients. Different patterns of EGFR mutations (according to EGFR co-mutation with different downstream pathway genesets) were used to group EGFR mutation population. Estimated infiltration analyses were used to explore changes in the immune microenvironment. Results: This study analyzed somatic mutation data from 1287 patients from five cohorts (TCGA, Broad, The Tumour Sequencing Project, Memorial Sloan Kettering Cancer Center, Catalogue Of Somatic Mutations In Cancer database). The probability of EGFR mutation was approximately 14.30% (184/1287) and the co-mutation rate was 11.41% (21/184) in patients with EGFR mutations. Glycosaminoglycan-related pathways were significantly upregulated in the EGFR mutant group. EGFR -mutated patients had lower TMB and PD-L1 protein levels than those in wild-type patients. Increase immature DCs infiltration and decreased NK CD56dim, T gamma delta, cytotoxic, and Th2 cell infiltration were the main immune changes in EGFR -mutated patients. Patients with EGFR -MAPK co-mutations had higher levels of TMB and PD-L1 protein expression. Meanwhile, the co-mutated patients had a similar immune microenvironment as that in wild-type patients. Conclusion: In this study, we defined a subgroup of patients with EGFR -MAPK co-mutations. These co-mutated patients may benefit from ICI treatment.
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