Abstract 2679: Role of TH2 cells in pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells remain largely unexplored. Here, we explored the role of oncogenic Kras (KrasG12D=Kras*) in pro-tumorigenic signaling interactions between cancer cells and host cells. We found that TH2 cells infiltrate the pancreas in the early stage of the tumorigenesis and secrete type 2 cytokines [interleukin (IL)4 and IL13]. Further, Kras* signaling is involved in establishing this paracrine circuit utilizing type 2 cytokines in the PDAC tumor microenvironment (TME)2. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC. This study and the work of others expanded the role of immune cell derived cytokines in the context of Kras* driven PDAC through its promotion of cancer cell proliferation. Importantly, perturbation of the IL4 and/or IL13 mediated signaling restricts tumor growth and increases survival in a mouse model of PDAC. Notably, PDAC patients with predominantly TH2 (Gata3+) polarized lymphoid cell infiltration show reduced survival compared to tumors with higher TH1 (Tbet+) cells. Finally, the presence of TH2 cells in the PDAC TME might explain the immense immunotherapy resistance observed in PDAC patients and anti-TH2 treatment might sensitize these patients to immune checkpoint inhibitors. Our subsequent preliminary work identified a potent inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2 and other immune cells such as Tregs. Inhibition of IL33 leads to a decrease in the infiltration and activation of TH2 cells and Treg cells, accompanied by significant PDAC tumor regression. Citation Format: Aftab Alam, Maulasri Bhatta, Parker Denz, Eric Levanduski, Prasenjit Dey. Role of TH2 cells in pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2679.