Abstract PO-049: Inhibiting MNK kinases promotes macrophage immunosuppressive phenotype to limit anti-tumor immunity

Abstract

Abstract 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. Select MNK kinase inhibitors are currently being evaluated in clinical trials for different tumor types. Their immunomodulatory effects in tumors with low infiltrating CD8+ T have not been clearly defined. Methods: In vivo efficacy of MNK kinase inhibitors (CGP57380 and eFT508), either as a single agent or in combination with anti-PD-1 or anti-CSF-1R antibody, was tested in syngeneic mouse models of pancreatic cancer. Tumor-associated macrophages (TAMs) and murine bone marrow-derived macrophages (BMDMs) were evaluated in vitro for modulation of their polarization by MNK kinase inhibitors and their suppression of co-cultured T cells. Markers of M1/M2 polarization were measured by qRT-PCR. The effects of MNK kinase inhibitors on the expression of select M2 markers were also evaluated in ex vivo slice cultures of human pancreatic tumors. Results: We first found an inverse relationship between MNK kinase activity and CD8+ T cell abundance in human pancreatic tumors. In tumor-bearing mice, while pharmacological inhibition of MNK kinase activity increased CD8+ T cell infiltration, the tumor-infiltrating CD8+ T cells lacked effector function and failed to mount anti-tumor responses. Mechanistically, we showed that systemic inhibition of MNK kinases increased the expression of several anti-inflammatory genes in BMDMs and potentiated the ability of BMDMs and TAMs to suppress T cell proliferation. Reversal of T cell exhaustion either by an anti-PD-1 antibody or by TAM depletion with an anti-CSF-1R antibody enhanced the anti-tumor efficacy of MNK inhibitors and prolonged animal survival. Importantly, treating ex vivo human pancreatic cancer slice cultures with MNK inhibitors led to increased expression of known immunosuppressive markers in TAMs. Conclusion: Together, these findings provide new insights into the effects of MNK kinase inhibition on CD8+ T cell infiltration and TAM function and identify combination regimens with MNK kinase inhibitors to achieve effective anti-tumor responses in pancreatic cancer patients whose tumors have a low number of functional CD8+ T cells. Citation Format: Thao N. D. Pham, Christina Spaulding, Mario A. Shields, Mahmoud G. Khalafalla, Daniel R. Principe, David J. Bentrem, Hidayatullah G. Munshi. Inhibiting MNK kinases promotes macrophage immunosuppressive phenotype to limit anti-tumor immunity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-049.