Activating Immune Recognition in Pancreatic Ductal Adenocarcinoma Using Autophagy Inhibition, MEK blockade and CD40 Agonism

Abstract: BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDA) patients have not yet benefitted from the revolution in cancer immunotherapy due in large part to a dominantly immunosuppressive tumor microenvironment (TME). MEK inhibition combined with autophagy inhibition leads to transient tumor responses in some PDA patients. We examined the functional effects of combined MEK and autophagy inhibition on the PDA immune microenvironment and the efficacy of synergizing the combined inhibition of MEK and autophagy with CD40 agonism against PDA using immunocompetent model systems. METHODS We implanted immunologically “cold” murine PDA cells orthotopically in WT C57BL/6J mice. We administered combinations of inhibitors of MEK1/2, inhibitors of autophagy and CD40 agonism and measured anticancer efficacy and immune sequel using mass cytometry (CyTOF) and CODEX multiplexed immunofluorescence imaging analysis to characterize the TME. We also used human and mouse PDA cell lines and human macrophages in vitro, to perform functional assays to elucidate the cellular effects induced by the treatments. RESULTS We find that co-inhibition of MEK (using cobimetinib, COBI) and autophagy (using mefloquine, MFQ), but not either treatment alone, activates the STING/Type I Interferon pathway in tumor cells which in turn activates paracrine tumor associated macrophages (TAMs) toward an immunogenic M1-like phenotype. This switch is further augmented by a CD40 agonism (aCD40). Triple therapy (COBI+MFQ+aCD40) achieved cytotoxic T cell activation in an immunologically “cold” mouse PDA model, leading to enhanced anti-tumor immunity. CONCLUSIONS MEK and autophagy co-inhibition coupled with CD40 agonism invokes immuno-repolarization and is an attractive therapeutic approach for PDA immunotherapy development.