Abstract IA06: Oncogenic Ras control of the tumor immune microenvironment

Abstract

Abstract Despite RAS proteins being exceptionally well-validated cancer targets, little progress has been made towards targeting them effectively in the clinic. We have optimized combination targeting of effector pathways downstream of RAS for specific activity on KRAS mutant cells, with combinations targeting MEK, IGF-1R and mTORC1 being highly effective in preclinical models. Replacing MEK with G12C KRAS inhibitor reduces the toxicity of the combination. However, these combinations are not able to eradicate tumors, which recur once treatment is stopped. In order to improve the effectiveness of RAS-targeted therapies, we have investigated the mechanisms whereby RAS signaling pathways can promote local immune suppression in the tumor microenvironment through inducing the expression of immune checkpoint proteins, immune suppressive cytokines, and extracellular enzymes. One such pathway involves the control of mRNA stability of PD-L1 and multiple cytokines by the 3′AU rich element binding protein, tristetraprolin. Another pathway that appears to be strongly upregulated in RAS mutant tumors is signaling by extracellular adenosine, which is strongly immunosuppressive. In order to test potential combinations of targeted therapies and immunotherapies resulting from these studies, we have developed new mouse models for KRAS mutant lung cancer that show more realistic interaction of the immune system with the tumor, which is not seen in existing genetically engineered mouse models used to study RAS mutant cancer due their lack of tumor heterogeneity and mutational burden. This work also involves detailed analysis of the tumor immune microenvironment using imaging mass cytometry and comparison between manipulatable mouse models and human clinical samples from the TRACERx lung cancer study. Citation Format: Julian Downward. Oncogenic Ras control of the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA06.