Abstract 1609: Targeting the oncogenic MAP4K4 regulatory axis in pancreatic cancer tumor microenvironment

Pancreatic Ductal Adenocarcinoma (PDAC) remains remarkably lethal, with a 5-year survival rate of less than 12%. Due to its widespread resistance to conventional therapy, PDAC is expected to be the second most common cause of cancer-related death in the United States by 2030. One of the major impediments to therapeutic failure in PDAC is the presence of an immunosuppressive tumor microenvironment (TME). We examined the function of Mitogen-activated protein kinases (MAPKs) upstream member, MAP4K4, in the PDAC-TME and tested the efficacies of MAP4K4 inhibitor and immunotherapy to overcome PDAC tumor burden. The role of MAP4K4 in regulating innate and adaptive components of PDAC-TME was determined in vivo using a preclinical immunocompetent murine model (i.e., in KPC) of PADC. The genes related to T cell dysfunctions were determined by the RT2 PCR array. Flow cytometry analyses were performed to determine the immune checkpoint proteins and cytotoxic cytokines in T cells. The therapeutic efficacy of MAP4K4 inhibitor and agonists of 4-1BB and OX40 was determined in the murine model of PDAC. The IHC analyses showed that overexpression of MAP4K4 increases tumor infiltration of macrophages and neutrophils and decreases T cells in the murine model of PDAC. Furthermore, treating PDAC mice with MAP4K4 pharmacological inhibitor GNE-495 decreased tumor-infiltrating macrophages and neutrophils and increased T cell counts. However, the GNE-495 treatment increased tumor-infiltrating T cells and was not associated with increased cytotoxicity of T cells. The RT2 PCR array analysis showed that treatment of GNE-495 decreased 4-1BB gene expression in peripheral and tumor-infiltrating T cells. The combined therapy of GNE-495 and 4-1BB agonistic mAb showed noticeable tumor regression and increased survival in the preclinical model of PDAC. Our study suggests that MAP4K4 regulates innate and adaptive immune cells in pancreatic-TME, and pharmacological inhibition of MAP4K4 decreases tumor macrophages and neutrophil counts. Moreover, the rationalized approach of combining a MAP4K4 inhibitor and a 4-1BB agonist mAb induced a T cell-mediated antitumor response, and this combination could serve as a viable treatment for PDAC. Citation Format: Sunil Singh, Sandeep Kumar, Saket Jha, Harsh Vyas, Piush Srivastava, Rakesh S. Nair, Basabi Rana, Ajay Rana. Targeting the oncogenic MAP4K4 regulatory axis in pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1609.