Abstract A35: Ovarian cancer stem cells subvert tumor-specific T cells by disrupting T cells’ metabolic fitness

Abstract

Abstract Cancer stem cells (CSCs) are defined by their unlimited self-renewal ability and their capacity to initiate and maintain malignancy, traits that are not found in most cells that compose the tumor. These stem cells have been shown to be relatively resistant to conventional chemotherapeutic regimens and radiation. Previously, we have reported that spheroid cells derived from 3D epithelial ovarian cancer cells are enriched with cancer stem cells by in vitro and in vivo experiments. In addition, we have demonstrated that CSCs adopt unique metabolic pathways by routing glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of rerouting glucose for anabolic purposes. In the current study, we hypothesized that CSCs may contribute to the immunosuppressive microenvironment of ovarian cancer by disrupting the metabolic fitness of infiltrating T cells. We isolated fresh spheroid cells from ovarian cancer patients’ ascites and examined their effect on T-cell responses ex vivo. In addition, other than ovarian cancer, we generated more spheroid cells from pancreatic cancer and breast cancer cells. Compared to nonspheroid cells, these spheroid cells have upregulated stem cell gene expression, higher ALDH activity, and more tumor-initiating capacities in SCID mice, indicating CSCs enrichment in spheroid cells. Seahorse XF analysis revealed a glycolytic metabolic phenotype of spheroid cells with increased extracellular acidification rate (ECAR) compared to nonspheroid cells. Spheroid cells suppress the response of cocultured T cells to TCR stimulation by inhibiting T-cell activation, growth, proliferation, and function independent of cell-cell contact determined by transwell assay and supernatant incubation. After spheroid cells treatment, activated T cells metabolically shifted from energetic to quiescence phenotype, which is reversely correlated with increased glycolysis in spheroid cells, indicating that highly glycolytic spheroid cells suppress T-cell response through reprogramming T-cell metabolic status. Furthermore, we found that spheroid cells dampen T cells’ response by inhibiting Erk-AKT-mTor signaling and by activating the integrated stress response pathway. This study provides novel insights into the relationship between cancer stem cells and T cells’ response and has clinical implications for cancer therapy. Citation Format: Feng Qian, Jianqun Liao, Anthony J. Miliotto, Katherine A. Collins, Kunle Odunsi. Ovarian cancer stem cells subvert tumor-specific T cells by disrupting T cells’ metabolic fitness. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A35.