Bioengineered Pancreatic Cancer Immunosuppressive Microenvironment Models for Screening Immunotherapies.

Abstract

Pancreatic cancer is notably resistant to treatment, primarily due to its dense desmoplastic stroma and immunosuppressive microenvironment. Accurately modeling this complex landscape and its immunosuppressive hallmarks in vitro is highly valuable for screening immunotherapeutic strategies. However, replicating these intricate features remains a significant challenge. Herein, we bioengineered miniaturized tumor-stroma platforms that combine cancer and stromal cells, as well as extracellular matrix mimetic biomaterials as a strategy to emulate the native tumor composition and key tumor immunosuppressive signatures. Bioengineered stratified tumor-stroma pancreatic cancer models, so termed cancer-on-a-bead platforms are generated in superhydrophobic surfaces and co-cultured with T cells, dendritic cells, as well as M0 macrophages, as a strategy to recapitulate tumor-immune interplay. The generated models revealed suppression of antigen presentation, M2 macrophage polarization, and T cell exhaustion, representing key features of this neoplasia. The screening of antibody mediated immunotherapy in the 3D tumor platforms, using clinically approved anti PD-1 antibody as a model therapeutic, partially restored T cell function. Overall, our findings demonstrate compartmentalized tumor-stroma models potential for being used to screen candidate immunotherapeutics for pancreatic cancer in a preclinical setting.