A Tumor Microenvironment Model of Pancreatic Cancer to Elucidate Responses Toward Immunotherapy.

Pancreatic cancer is a devastating malignancy with minimal treatment options. Standard-of-care therapy, including surgery and chemotherapy, is unsatisfactory, and therapies harnessing the immune system have been unsuccessful in clinical trials. Resistance to therapy and disease progression are mediated by the tumor microenvironment, which contains excessive amounts of extracellular matrix and stromal cells, acting as a barrier to drug delivery. There is a lack of pre-clinical pancreatic cancer models that reconstruct the extracellular, cellular, and biomechanical elements of tumor tissues to assess responses toward immunotherapy. To address this limitation and explore the effects of immunotherapy in combination with chemotherapy, we developed a multicellular 3D cancer model using a star-shaped poly(ethylene glycol)-heparin hydrogel matrix. Human pancreatic cancer cells, cancer-associated fibroblasts, and myeloid cells were grown encapsulated in hydrogels to mimic key components of tumor tissues, and cell responses toward treatment were assessed. Combining the CD11b agonist ADH-503 with anti-PD-1 immunotherapy and chemotherapy led to a significant reduction in tumor cell viability, proliferation, metabolic activity, immunomodulation, and secretion of immunosuppressive and tumor growth-promoting cytokines. This article is protected by copyright. All rights reserved.