Bioprinted 3D vascular cancer model

About This Grant

The activity of T cells is key to anti-tumor immunity, but T cells frequently exhibit poor penetration into solid tumors and a dysfunctional phenotype. Preclinical studies typically utilize mouse models to study these processes, but even humanized mouse models do not capture key aspects of human biology relevant to immunotherapies. Here we will develop a 3D model of human cancer biology to enable studies of T cell trafficking within tumors, their engagement with dendritic cells (DCs) in activation niches, and their killing of cancerous cells. We will use µPOROUS embedded printing to fabricate these models. We will first create 3D models of mouse cancer, due to the ready availability of isogenic cancer, DCs and T cells, and reagents to analyze murine DCs and T cells. We will then create the human models, including tumor, vascular and immune cells derived from the same patient. Together, the murine and human models will be used to explore two key questions that are difficult to study in vivo: (1) the impact of changing matrix viscoelasticity on DC-T cell interaction, and (2) the role of the activation niche in T effector function. The following specific aims will be pursued: (Aim 1) Utilize µPOROUS embedded printing to develop in vitro murine and human cancer models that include vascular conduits for T cell entry, a stromal compartment that enables T cell migration similar to that found in vivo, and a central tumor compartment consisting of either murine isogenic (B16F10) or human HLA-matched melanoma. (Aim 2) Study how the viscoelasticity of the matrix impacts the ability of type 1 conventional dendritic cells (cDC1s) to activate, in an antigen-specific manner, T cells migrating through the model stroma. (Aim 3) Determine the impact of activation niches on T cell phenotype and cytotoxic function, and validate the ability of the system to model the role of checkpoint blockade therapy. At the completion of this project we will have developed novel, 3D models of both mouse and human tumors that will allow replication of key aspects of cancer immunotherapy. Beyond addressing two key questions in T cell biology and performing initial validation, these models will enable more realistic investigation of human tumor - DC - T cell interactions in a 3D setting, including the preclinical evaluation of novel immunotherapy strategies.