RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment

Abstract

The rat sarcoma virus (RAS) gene is the most commonly mutated oncogene in cancer, with about 19% of cancer patients carrying RAS mutations. Studies on the interaction between RAS mutation and tumor immune microenvironment (TIM) have been flourishing in recent years. More and more evidence has proved that RAS signals regulate immune cells' recruitment, activation, and differentiation while assisting tumor cells to evade immune surveillance. This review concluded the direct and indirect treatment strategies for RAS mutations. In addition, we updated the underlying mechanisms by which RAS signaling modulated immune infiltration and immune escape. Finally, we discussed advances in RAS-targeted immunotherapies, including cancer vaccines and adoptive cell therapies, with a particular focus on combination strategies with personalized therapy and great potential to achieve lasting clinical benefits.

Keywords: Adoptive cell therapy; Cancer vaccine; Immune cell infiltration; Immune escape; RAS mutation.

Fig. 1

Overview of RAS mutation data. A The proportion of RAS mutation hotspots from TCGA database. B G12, G13, and Q61 occupy over 85% of all RAS mutations according to COSMIC database

Fig. 2

The influence of mutant RAS on the tumor immune microenvironment. RAS mutant cancer cells not only regulate tumor-associated immune response at the level of recruitment, activation, and differentiation of immune cells, but also induce cancer cells to escape immune surveillance via upregulating PD-L1 and CD47 signals. Together, these alterations shape an immunosuppressive state, and present opportunities for intervention in the treatment of RAS-mutated malignancies

Fig. 3

RAS signaling pathways with targeting strategies. RAS mutations mainly lead to uncontrolled activation of the MAP kinase pathway and PI3K pathway. Indirect strategies for targeting RAS include the inhibition of RAS membrane localization, suppression of SHP2/SOS1 and blockage of downstream signal. Direct strategies for targeting RAS include small molecular inhibitors for RAS proteins, genetic engineering technology and RAS degraders

Fig. 4

Immunotherapy regimens for RAS mutant cancers. A By injecting peptide, mRNA, and DC-based vaccines, the activated T cell receptor (TCR) binds to the major histocompatibility complex (MHC). The powerful antigen–antibody response eventually leads to cancer cell death. B Peripheral blood T cells from cancer patients are genetically modified by viral vectors to create CAR-T and TCR-T cells that express patient-specific, RAS-driven cancer cell neoantigens. The patient-specific tumor-infiltration active T cells (TILs) are isolated and expanded ex vivo. The most tumor-specific and functionally enriched T cells are administered to the patient once lymphodepletion