Abstract LBA024: IL-36γ induces immune infiltration and suppresses tumor growth in a syngeneic mouse model for pancreatic cancer

Abstract

Abstract Pancreatic cancer (PC) is one of the most aggressive and lethal types of cancer. It is the third leading cause of cancer-related mortality in U.S., accounting for 6% of annual death. Immunotherapeutic strategies such as immune checkpoint inhibitors have shown great success in a number of tumor types, but only with limited activity in patients with PC. Pancreatic tumor is characterized by the presence of dense stromal tissue which primarily consists of immune-suppressive fibroblasts. The immune microenvironment remains dysfunctional due to the lack of tumor infiltrating lymphocytes (TILs) and immune stimulatory molecules. Proinflammatory cytokines play a pivotal role in regulating tumor immunogenicity and antitumor immunity. Elucidating the role of proinflammatory host mediators can contribute to the development of new therapies for PC. IL-36γ, a proinflammatory mediator is important for the IL-23/IL-17-dominated inflammation and induces Th1 immune responses. The role of IL-36γ in pancreatic tumor immunity has not been well studied. In this study, we examined the expression and functional regulation of IL-36γ in PC cells and found that IL-36γ cytokine treatment induces immune infiltration and suppresses tumor growth in a murine PC model. Immunohistochemical (IHC) analysis of pancreatic ductal adenocarcinoma (PDAC) specimens showed minimal IL-36γ positive staining, thus indicating very low expression of IL-36γ in PDAC. Intratumoral treatment with recombinant IL-36γ in a syngeneic mouse model of PDAC significantly inhibited tumor growth (57.8% inhibition after two weeks of treatment) without any significant animal weight loss compared to the vehicle control. Flow cytometry analysis showed increased infiltration of lymphocyte subsets (CD45+ and CD3+ cells) in tumors derived from the IL-36γ treated mice. Further studies are ongoing to investigate the effect of IL-36γ treatment on dendritic cells and macrophages in PDAC tumors. Our study establishes the potential role of IL-36γ in promoting antitumor immune responses and lay the foundation for clinical application in PC (This work was supported by TGen’s Women Philanthropy Council). Citation Format: Kuntal Halder, Daniel D Von Hoff, Haiyong Han. IL-36γ induces immune infiltration and suppresses tumor growth in a syngeneic mouse model for pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA024.