MAP4K4 调控胰腺肿瘤微环境的免疫格局，并为免疫治疗提供了机会

Due to its widespread resistance to conventional therapy, Pancreatic Ductal Adenocarcinoma (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).

Here, we report the effect of MAP4K4 in regulating innate and adaptive immunity in PDAC-TME in KPC tumors. The IHC analyses revealed that the overexpression of MAP4K4 enhances tumor infiltration of macrophages and neutrophils, while decreasing the number of T cells in KPC PDAC tumors.

Furthermore, treating KPC mice with the MAP4K4 pharmacological inhibitor GNE-495 decreased the number of tumor-infiltrating macrophages and neutrophils and increased T cell counts. The RT 2 PCR array analysis revealed that treatment with GNE-495 decreased the expression of the co-stimulatory receptor 4-1BB gene in both peripheral and tumor-infiltrating T cells.

The combined therapy of GNE-495 and a 4-1BB agonistic monoclonal antibody (mAb) demonstrated the presence of maximal cytotoxic T cells and tumor regression, associated with increased survival in KPC mice.

Our study suggests that MAP4K4 regulates innate and adaptive immune cells in pancreatic TME, and pharmacological inhibition of MAP4K4 decreases tumor macrophage and neutrophil counts.

Moreover, the rationalized approach of combining a MAP4K4 inhibitor and a 4-1BB agonist mAb induces a T cell-mediated antitumor response, and this combination could serve as a viable treatment for PDAC.