Shaping the battlefield: EGFR and KRAS tumor mutations’ role on the immune microenvironment and immunotherapy responses in lung cancer

Abstract

The two most common and mutually exclusive driver mutations in non-small cell lung cancer affect EGFR and KRAS oncogenes. While EGFR mutations typically arise in non-smokers and are correlated with non-inflamed tumor microenvironment, KRAS mutations are associated with tobacco smoking, high mutational burden, and immunologically more active tumors. Consequently, current cancer immunotherapies have failed in patients with EGFR mutations, while patients with KRAS mutations have more favorable outcomes. The distinctive properties of the tumor immune microenvironment can partly explain the differences in the treatment outcomes. Besides the undeniable role of T lymphocytes, other immune cell types, cancer-associated fibroblasts, immunomodulatory cytokines, and angiogenesis are emerging as important players in these tumors. This article summarizes the current knowledge about the impact of EGFR versus KRAS mutations, among other mutations, on the tumor microenvironment and immunotherapy responses in lung cancer, highlighting the possible clinical implications for present and upcoming immunotherapy regiments, as well as emphasizing the gaps in the current knowledge that should be further investigated.