Abstract 3097: MNK1/2 kinase expression in immune cells dictates tumoral response to MNK inhibitors

Background: MAPK-interacting serine/threonine-protein kinase 1 and 2 (MNK1 and MNK2) are downstream effectors of the MEK/ERK and p38 MAPK pathways. Increased expression and activity of MNK kinases are linked to tumor growth and therapeutic resistance. As a result, several classes of MNK inhibitors (MNKi) have been developed and evaluated preclinically. Previously, we reported that treatment of murine pancreatic tumors with MNKi resulted in increased tumoral infiltration of PD-1hiCD8+ T cells. We further found that MNKi-induced increase in immunosuppressive tumor-associated macrophages (TAMs) accounted for the infiltrating T cell exhaustion. Finally, co-treatment with MNKi and anti-PD-1 rescued T cell activity and sufficiently controlled tumor growth. However, the extent to which MNKi efficacy relies on the immune cells was not clearly defined. In this study, we set out to better understand the roles of MNK kinases in T cells and macrophages, and how they contribute to MNKi anti-tumor efficacy. Methods: We evaluated the proliferation and effector functions of bone marrow-derived macrophages (BMDMs) and splenocyte-derived T cells collected from either mice with wild-type background or mice with body-wide knockout (KO) of MNK1, MNK2, or both MNK1 and MNK2 expression. In addition, we assessed murine pancreatic tumor growth in wild-type, MNK1-, MNK2-, or MNK1/2-KO and their response to anti-PD-1 therapy, either alone or in combination with MNKi. Results: We first found that BMDMs isolated from MNK1-, MNK2-, or MNK1/2-KO (collectively referred to as MNKKO hereon) mice are more potent at suppressing T cell proliferation in vitro. Interestingly, T cells isolated from MNKKO spleen demonstrated higher proliferative capacity and activation following CD3/CD28 ligation. Compared to the wild-type, MNKKO T cells are also capable of better proliferation when co-cultured with MNKKO BMDMs. Similarly, T cells isolated from the tumor-bearing MNKKO mice showed enhanced effector functions compared to those isolated from the wild-type mice. Significantly, tumor-bearing MNKKO mice showed an exceptional response to an anti-PD-1 antibody, whereas the wild-type mice did not respond to the treatment. Finally, the addition of a MNKi was found to potentiate anti-PD-1 therapy in the wild-type, but not the MNKKO, mice. Conclusion: Together, these new findings demonstrate previously unknown roles of MNK kinases in T cells, macrophages, and their crosstalk within the tumor microenvironment. These data also suggest that while MNKi have been designed to target cancer cells, their reported efficacy relies primarily on the immune cells, specifically T cells. Thus, efforts to enhance MNKi efficacy should focus on combining these drugs with immune-modulatory agents, particularly those that can boost T cell activity or suppress immunosuppressive macrophages. Citation Format: Thao D. Pham, Apurba Majumder, Alejandra M. Marinelarena, Jeffrey H. Becker, Hidayatullah G. Munshi. MNK1/2 kinase expression in immune cells dictates tumoral response to MNK inhibitors [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 3097.