Abstract SY42-01: Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche

Abstract

Abstract Tumor-initiating stem cells shape microenvironment into an immunosuppressive barrier and a pro-tumorigenic nicheLinheng Li Stowers Institute for Medical Research, Kansas City MO 64110Kansas University of Cancer Center, Kansas City KS 66160 Accumulated evidence supports the concept that tumor-initiating stem cells (TSCs) are at the root of tumor/cancer and are largely responsible for the commonly observed resistance to chemoradiotherapy (CRT) and frequent relapse of disease. How a subset of TSCs, or therapy resistant TSC (TrTSC), survives and supports tumor regrowth post treatment is a fundamental biological question and clinically unsolved problem. Recently, we utilized single-cell RNA-sequencing to identify therapy resistant TSCs (or TrTSCs) in mouse models of CRT-challenged intestinal adenoma, followed by bioinformatics analysis to reveal the bidirectional crosstalk that occurs between TSCs and the tumor microenvironment (TME). The results of the analysis indicate that TSCs shape the TME into an immunosuppressive barrier. Particularly, TrTSCs recruit tumor-associated monocytes and macrophages (TAMMs), which in turn, via Cox-2 dependent prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, induce Akt-mediated phosphorylation of β-catenin and thus enhance the β-catenin activity. Furthermore, we show that enhanced β-catenin signaling upregulates multiple immune-checkpoint genes, thus empowering the immune escape capabilities of TSCs. Taken together, overcoming both the extrinsic immunosuppressive barrier and intrinsic immune escape has the potential to increase the efficacy of checkpoint inhibition therapies against cancers in the future. Citation Format: Linheng Li. Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY42-01.