Inhibition of SUMOylation modulates the immunosuppressive microenvironment of pancreatic cancer

Abstract

Abstract Objective Pancreatic cancer (PC) is a highly aggressive disease that is poorly responsive to available immunotherapy approaches, such as checkpoint inhibitors. Post-translational protein modification (PTM) by small ubiquitin-like modifier (SUMO) is upregulated in cancer, and high expression of SUMOylation-related factors correlates with poor survival in PC. TAK-981 is a novel inhibitor of SUMOylation that has demonstrated induction of anti-tumor immune responses in preclinical models. Our hypothesis is that TAK-981 will decrease SUMOylated proteins and subsequently modulate the tumor microenvironment to increase anti-tumor immunity. Methods In order to recapitulate the microenvironment of human PC, a 3-dimensional organoid cell line derived from a genetically-engineered “KPC” mouse was used. Organoids were injected orthotopically into the head of the pancreas via laparotomy. Once tumors reached 5–7 mm in diameter on ultrasound imaging, mice were randomized to one of two treatment groups: Control/Vehicle versus TAK-981 (15 mg/kg) delivered daily via intraperitoneal injection. Tumors were harvested on day 14 for gene expression analysis by quantitative real time PCR (RT-qPCR). Results Tumor growth (Fig. 1) in the TAK-981 15 mg/KG daily group (mean + SD volume = 207 + 109 mm3) was significantly inhibited compared to the vehicle group (595 + 141 mm3, p < 0.01). Immunohistochemical staining for CD 31 (Fig. 2) and Caspase 3 indicated a reduction of angiogenesis and increased apoptosis of tumor cells, consistent with the well-established roles of SUMOylation in angiogenesis and tumorigenesis. Gene expression analysis of tumor lysates showed a 26-fold increase in expression of Interferon beta (p<0.05), and an almost 2-fold increase in expression of genes related to dendritic cell activation, including CD80 (p<0.05) and CD86 (p=0.14) in the TAK-981 group, suggesting a modulation of the immune microenvironment. Conclusion Our results suggest that the inhibition of SUMOylation with TAK-981 is associated with improved local tumor control and changes in the immunosuppressive tumor microenvironment. We expect that TAK-981 will improve PC responsiveness to immunotherapy, such as with checkpoint inhibitors.