Combination Therapy with a Hypomethylating Drug (Decitabine) Plus an Immune Checkpoint Inhibitor (Anti-PD-1H) in the KPC Mouse Model of Pancreatic Cancer

Abstract

Background: Treatment with single-agent decitabine (5aza-dC; DAC), a well-tolerated DNA hypomethylating drug, in a mouse model of PDAC, KPC-Brca1, extended the survival of the animals and upregulated immune-related pathways. We now follow up these findings using DAC followed by the immune checkpoint inhibitor anti-PD-1H in the KPC (Pdx-Cre Kras/p53) model. Methods: We treated tumor-bearing KPC mice with DAC, and with an anti-PD-1H monoclonal antibody, separately and in combination, and assessed tumor growth kinetics by high resolution ultrasound imaging, mouse survival, immune cell infiltration of the tumors by quantitative immunohistochemistry and immunofluorescence, and gene expression in the tumors by RNA-Seq. Mice with a 3-5 mm tumor were enrolled in treatment studies. Outcome measures were tumor growth and overall survival. Results: Treatment with single-agent DAC led to increased tumor-infiltrating CD8+ T cells and tumor necrosis, and a significant reduction in tumor growth. Tumor infiltrating PD-1H-expressing T cells were significantly increased following DAC treatment, and the hypomethylating drug led to recruitment into the tumors of a novel population of macrophage-lineage cells. Anti-PD-1H therapy alone had only modest effects on tumor growth, but DAC treatment followed by anti-PD-1H was associated with increased inhibition of tumor growth and a significant prolongation of mouse survival (median survival of 26.5 days vs 41 days; p=0.001). Conclusions: Therapy with DAC alone, and DAC plus anti-PD-1H, in the KPC mouse model of PDAC inhibits tumor growth and produces changes in lymphocyte and myeloid cell populations in the tumor microenvironment, with a significant benefit from combining the two agents. These positive findings provide a basis for future studies of DAC combined with other immune checkpoint inhibitors as treatment for PDAC.