A Tumor Microenvironment Model of Pancreatic Cancer to Elucidate Responses toward Immunotherapy

Area of Science:

• Oncology
• Biomedical Engineering
• Immunotherapy

Background:

• Pancreatic cancer has limited treatment options, with standard therapies and immunotherapies showing limited success.
• The tumor microenvironment, characterized by dense extracellular matrix and stromal cells, impedes drug delivery and contributes to treatment resistance.
• Existing preclinical models lack the complexity to accurately represent the tumor microenvironment for immunotherapy assessment.

Purpose of the Study:

• To develop a multicellular 3D pancreatic cancer model that recapitulates key aspects of the tumor microenvironment.
• To evaluate the efficacy of a combination therapy involving immunotherapy and chemotherapy in this advanced model.
• To investigate the impact of this combination therapy on tumor cell behavior and the tumor microenvironment.

Main Methods:

• Development of a star-shaped poly(ethylene glycol)-heparin hydrogel for creating a 3D matrix.
• Encapsulation of human pancreatic cancer cells, cancer-associated fibroblasts, and myeloid cells within the hydrogel to form a multicellular tumor model.
• Assessment of cell responses to treatment, including viability, proliferation, metabolic activity, and cytokine secretion.

Main Results:

• The combination of CD11b agonist ADH-503, anti-PD-1 immunotherapy, and chemotherapy significantly reduced pancreatic tumor cell viability and proliferation.
• This combination therapy modulated the immune response and decreased the secretion of immunosuppressive and tumor-promoting cytokines.
• The 3D model successfully mimicked key tumor tissue components and allowed for the assessment of therapeutic effects.

Conclusions:

• The developed 3D pancreatic cancer model provides a more realistic platform for evaluating novel therapeutic strategies.
• Combination therapy, including ADH-503, anti-PD-1 immunotherapy, and chemotherapy, shows significant promise in overcoming treatment resistance in pancreatic cancer.
• This approach offers a potential new avenue for improving treatment outcomes in pancreatic cancer by targeting both tumor cells and the tumor microenvironment.