Role of type 2 immune response in pancreatic cancer tumorigenesis

Abstract public domain (NIH RePORTER)

Project Summary: 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. In a recent study, we demonstrated that cytokines, IL4 and IL13, secreted by TH2 cells (a subtype of CD4+ T cells), provide trophic support for PDAC development. Mechanistically, inhibiting this cytokine mediated crosstalk between cancer-TH2 cells either genetically or pharmacologically drastically reduces tumor growth and increases survival in a preclinical model. 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 innate lymphoid cells 2 (ILC2) and Tregs. Importantly, we found that the release of IL33 by PDAC cells is mediated by intratumor mycobiome. Inhibition of IL33 or anti-fungal treatment leads to a decrease in the infiltration and activation of type 2 immune cells (TH2 and ILC2) and Treg cells, accompanied by significant PDAC tumor regression. Taking these observations together, we hypothesize that type 2 immune response plays an important role in PDAC tumorigenesis and intratumor mycobiome is key to the IL33 secretion. The major objective of this proposal is to elucidate the role of mycobiome in the IL33 mediated type 2 immune response and provide pre-clinical evidence to guide future clinical studies with an anti-IL33 monoclonal antibody in PDAC patients. To that end, we will determine the molecular mechanism of mycobiome mediated IL33 release in cell and organoid models of PDAC. Further, to conduct a clinically relevant study, we will analyze IL33, intratumor mycobiome and type 2 immunocytes in the PDAC patient tumor and serum samples. While our preliminary studies using the syngeneic orthotopic model have shown a significant tumor regression upon IL33 deletion or anti-fungal treatment, synergistic combination strategies are expected to be even superior in efficacy. So, we propose to use an anti-IL33 antibody in combination with anti-fungal treatment for superior efficacy. Finally, to block the IL33-TH2/ILC2 axis we have three genetically engineered mouse models that will allow rigorous testing of the function of IL33 in PDAC tumorigenesis. In conclusion, our study is poised to identify a novel strategy to target PDAC patients and provide mechanistic insights for future clinical development of anti- IL33 therapy.

Public health relevance public domain (NIH RePORTER)

Project Narrative: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030. We recently showed that TH2 cells produce type 2 cytokines (IL4 and IL13) that provide trophic support to PDAC tumorigenesis. In this proposal, we aim to understand the mycobiome mediated cancer cell-TH2 axis and explore the therapeutic potential of inhibiting this axis for PDAC treatment.