Unveiling the role of KRAS in tumor immune microenvironment

Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as “undruggable”. KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a “molecule switch” determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a “hot” TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a “colder” TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect. ● KRAS mutation characterize with an immune suppressive tumor microenvironment. ● KRAS mutant NSCLC especially KRAS G12C respond better to immune checkpoint inhibitor. ● Different Co-mutations differ in microenvironment profiles and responses to therapies. ● KRAS inhibitors exhibit potential synergistic effect with immune checkpoint inhibitors. ● Other therapeutic strategies with immunomodulatory functions are under development.