Dendritic cells (DC) are responsible for initiating the most antigen-specific immune responses. In particular, DCs form an immunological synapse with T cells, orchestrated by three main signals, which forms the basis for antigen-specific immune responses. For high-throughput production of T cells specific to sub-dominant tumor- associated antigens, DC-like biological and mechanical properties should be emulated in culture platforms used for T cell expansion. The existing culture platforms with DC-like properties are made of rigid materials, which disable the movement of effector molecules required for T cell receptor clustering and thus remain inefficient in activating T cells. The central goal of this proposal is to fabricate synthetic DCs out of matrices whose mechanical properties are optimized for maximal expansion of antigen-specific central memory T cells. This research is organized around two key goals: (1) to develop mechanically optimized synthetic DCs providing three signals for efficient T cell expansion, and (2) to fabricate the stiffness-optimized synthetic micro-DCs for T cell growth in the form of 3D microcapsules. Successful completion of the proposed aims will provide a new paradigm for expanding T cells against individualized tumor-specific mutational antigens through interaction with novel mechanically optimized synthetic DCs. While this project is `high-risk', given the novel integration of biological and mechanical signals through synthetics DCs, it will launch a new direction for T cell manufacturing and may lead to `high-payoff' outcomes in the fields of immunoengineering and immunotherapy.
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumors. An efficient and robust anticancer immune response critically depends on robust activation and proliferation of helper, cytotoxic, and central memory T cells. However, the progress on this front has been hampered by the difficulty in expanding long-lived effector CD8+ T cells that are specific to the peptide presented by the tumors. Physical interaction of T cells with dendritic cells (DCs) leads to antigen-specific immune responses. This proposal develops matrix platforms mimicking biomechanical properties of DCs for the expansion for antigen-specific T cells.