Immunomodulation of Pancreatic Cancer via Inhibition of SUMOylation and the CD155/TIGIT Pathway

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth. We found that the CD-155/TIGIT pathway, a key regulator of immune evasion in PDAC, is influenced by SUMOylation. We hypothesized that the combination of SUMO E1 and TIGIT inhibition would synergistically induce anti-tumor immune effects. We used a clinically relevant orthotopic mouse model that consistently develops liver metastases to study this combination therapy alone and in the perioperative setting with surgical resection. The combination of SUMO E1 and TIGIT inhibition significantly prolonged survival. Complete responders exhibited protective immunity and enhanced T cell reactivity to model-specific alloantigens. Complementary immune analyses of resected tumors demonstrated that combination therapy more significantly reduces the abundance of regulatory FoxP3+CD4+ T cells than either monotherapy alone. Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of Tregs through innate immune cells, potentially by activation of type I interferon responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.