Immune modulatory effects of oncogenic KRAS in cancer

Abstract

Oncogenic KRAS mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic KRAS-downstream signalling is a main driver of carcinogenesis, there is increasing evidence that it also mediates autocrine effects and crosstalk with the tumour microenvironment (TME). Here, we discuss recent reports connecting KRAS mutations with tumour-promoting inflammation and immune modulation caused by KRAS that leads to immune escape in the TME. We discuss the preclinical work on KRAS-induced inflammation and immune modulation in the context of currently ongoing clinical trials targeting cancer entities that carry KRAS mutations and strategies to overcome the oncogene-induced effects on the immune system.

Fig. 1. Pro-inflammatory effects of KRAS-induced inflammation in cancer.

Pro-inflammatory effects mediated by the activation of transcription factors (STAT3), the production of cytokines (e.g., IL-6), the activation of NLRP3 inflammasome and the release of chemokines caused by oncogenic KRAS activation are listed. Representative immune cells in the tumour microenvironment (TME) affected by some of these signals are shown. The dotted line indicates co-occurring mutations.

Fig. 2. Effects of KRAS-induced immune modulation in cancer.

Multiple intracellular downstream effects of KRAS on chemokine production (CXCL3), cytokine production, MHC expression and ligand expression are shown. Mutations are indicated by a red star symbol (activating mutations in MYC, inactivating mutations in TP53 and STK11/LKB1). The dotted line indicates co-occurring mutations.