Related Experiment Video
Updated: Jan 9, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Immunomodulation of Pancreatic Cancer via Inhibition of SUMOylation and the CD155/TIGIT Pathway
Jorge De la Torre Medina1, Utsav Joshi1, Himangshu Sonowal1
1Division of Surgical Oncology, Departmen of Surgery, UC San Diego, San Diego, California.
Abstract:
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 antitumor 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 regulatory T cells through innate immune cells, potentially by activation of type I IFN responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.
Insights
Combining SUMO E1 inhibition with anti-TIGIT therapy shows promise for pancreatic cancer. This approach reprograms the tumor microenvironment, enhancing immune response and prolonging survival in preclinical models.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant challenge due to its immunosuppressive tumor microenvironment (TME).
- SUMOylation, regulated by SUMO E1 enzyme, influences immune evasion pathways in PDAC, including the CD-155/TIGIT axis.
Purpose of the Study:
- To investigate the synergistic anti-tumor effects of combined SUMO E1 and TIGIT inhibition in a preclinical PDAC model.
- To evaluate this combination therapy in a perioperative setting with surgical resection.
Main Methods:
- Utilized a clinically relevant orthotopic mouse model of PDAC with liver metastases.
- Assessed combination therapy efficacy, survival rates, immune cell populations (including Tregs), and T cell reactivity.
- Conducted mechanistic studies to elucidate the impact of SUMO E1 inhibition on immune responses.
Main Results:
- The combination therapy significantly prolonged survival compared to monotherapy.
- Complete responders demonstrated protective immunity and enhanced T cell responses.
- Combination therapy markedly reduced regulatory FoxP3+CD4+ T cells (Tregs), more effectively than single agents.
Conclusions:
- Combined SUMO E1 and TIGIT inhibition synergistically enhances anti-tumor immunity in PDAC.
- SUMO E1 inhibition may potentiate anti-TIGIT efficacy by promoting Treg elimination via innate immune cells and type I interferon responses.
- This strategy offers a potential mechanism to improve anti-TIGIT therapy outcomes in PDAC.
