Abstract A09: CD4 T cells mediated protumorigenic pathway in pancreatic cancer

Abstract

Abstract A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. This Kras*-driven heterotypic signaling circuit in the early and advance tumor microenvironment enables cooperative protumorigenic interactions in early steps of the neoplastic transformation process as well as in promoting growth of established tumors, providing novel therapeutic targets in the Kras* pathway for this intractable disease. Here, we explored the role of Kras* in protumorigenic signaling interactions between cancer cells and host cells in tumor microenvironment. Early-stage malignant lesions and advanced tumors show close proximity of Kras* expressing cancer cells and abundant invading TH2 (CD4+ Gata-3+) cells, which can produce IL-4 and IL-13. Single-cell analysis of low- and high-grade IPMN and PDAC patient samples revealed CD4+ T-cell infiltration and higher percentage of the CD4+ T cells are Gata3+ TH2 subtypes compared to T-bet+ TH1 cells. Similarly, imaging mass spectrometry analysis showed presence of CD4+ T cells in close proximity to cancer cells. Mechanistic studies identified Jak1-Stat6 as the primary signaling pathway downstream of IL-4/IL-13 activated IL-4 receptor complexes in cancer cells. Integrated transcriptomic and chromatin immunoprecipitation sequencing (ChIP-seq) profiling identified cMyc, specifically its upstream enhancer element, as a direct target of activated Stat6. Metabolomic analysis demonstrated that IL-4/13STAT6cMyc upregulation drives increased glycolysis along with upregulated expression of key glycolysis enzymes, forging a link between Kras*-driven glycolysis via paracrine activation of cMyc. Citation Format: Prasenjit Dey, Jun Li, Jianhua Zhang, Huamin Wang, Wen-Ting Liao, Vincent P Bernard, Giannicola Genovese, Anirban Maitra, Anders Strom, Ronald A. DePinho. CD4 T cells mediated protumorigenic pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A09.