KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas.

Abstract

Lung adenocarcinomas exhibit various patterns of genomic alterations. During the development of this cancer, KRAS serves as a driver oncogene with a relatively high mutational frequency. Emerging data suggest that lung adenocarcinomas with KRAS mutations can show enhanced PD-L1 expression and additional somatic mutations, thus linking the prospect of applying immune checkpoint blockade therapy to this disease. However, the responses of KRAS-mutant lung adenocarcinomas to this therapy are distinct, which is largely attributed to the heterogeneity in the tumoral immune milieus. Recently, it was revealed that KRAS-mutant lung adenocarcinomas simultaneously expressing either a LKB1 or TP53 mutation typically have different immune profiles of their tumours: tumours with a KRAS/TP53 co-mutation generally present with a significant upregulation of PD-L1 expression and tumoricidal T-cell accumulation, and those with a KRAS/LKB1 co-mutation are frequently negative for PD-L1 expression and have few tumoricidal immune infiltrates. In this regard, interrogating TP53 or LKB1 mutation in addition to PD-L1 expression will be promising in guiding clinical use of immune checkpoint blockade therapy for KRAS-mutant lung adenocarcinomas.