Inhibition of SUMOylation enhances responses to irreversible electroporation in pancreatic cancer. (28th May 2021)

• Record Type: Journal Article
• Authors: Erdem, S; Narayanan, J S; Worni, M; Chen, Y; White, R
• Is Part Of: British journal of surgery. Volume 108(2021)Supplement 4
• Publication Date: 2021-05-28
• Subjects: Surgery -- Periodicals; 617.005
• DOI: 10.1093/bjs/znab202.027
• Languages: English
• ISSNs: 0007-1323

Abstract

Abstract: Objective: The revolutionary results of immunotherapy have not yet translated to pancreatic cancer (PC). Irreversible electroporation (IRE) is a non-thermal ablative therapy that can generate tumor-specific immune responses, yet not sufficient to eradicate distant metastatic disease. Post-translational protein modification (PTM) by small ubiquitin-like modifier (SUMO) is involved in carcinogenesis and PD-L1 mediated immunosuppression. TAK-981 is a novel inhibitor of SUMOylation that has demonstrated induction anti-tumor immune responses in preclinical models. Our hypothesis is that TAK-981 will augment the effects of IRE in an immunocompetent orthotopic mouse model of PC. Methods: The PC cell line (KPC4580P) was derived from an autochthonous tumor arising in a genetically engineered mouse model (KPC). The tumors were implanted orthotopically into the pancreas via laparotomy. Once tumors reached 5-7 mm in diameter, mice were randomized to one of four treatment groups: IRE alone, TAK-981 alone, IRE + TAK-981, or no treatment. IRE versus sham laparotomy (150 x 90 microsec pulses at 1500 V/cm) was performed once through second laparotomy. TAK-981 (7.5mg/kg) versus vehicle was delivered via subcutaneous injection twice weekly x four doses, starting on the day of IRE. Tumors were harvested on day 14 for flow cytometric analysis. Results: Ultrasound was performed on days 8, 14 and 20 after initiation of treatment. Tumor growth in the IRE + TAK-981 group was significantly inhibited compared to sham-treated tumors (Fig. 1, *p=0.0002), and this effect persisted to day 20, even after treatment with TAK-981 was stopped on day 11 (p < 0.01). Flow cytometry revealed a greater than 2-fold increase in CD8+ T-cells (Fig. 2a, *p <0.05) and 4-fold increase in IFN-gamma+ CD8+ T-cells (Fig. 2b, *p=0.01) in tumors treated with the combination relative to sham-treated tumors. Conclusion: Our results suggest that the combination of IRE with TAK-981 is associated with better local tumor control and a significant increase of CD8+ T-cells and IFN-gamma+ CD8+ T-cells. We expect that this combination might contribute systemic immune responses that would prevent or even eradicate distant metastasis. Given that immunosuppression mediated by PD-L1 is regulated by ubiquitination and is seen in 50% of PC tumors, targeting PTM with TAK-981 might also render PC responsive to immunotherapy with checkpoint inhibitors.