Biomaterials for Targeted Modulation of Conventional Type 1 Dendritic Cells

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SUMMARY Immunotherapy has shown great promise to cure cancers, especially with the success of checkpoint blockades and chimeric antigen receptor (CAR) T cell therapies, but its utility is still limited by low patient response rate, poor efficacy against many solid tumors, and/or severe side effects. These issues motivate the development of new immunotherapy that can elicit potent and persistent cytotoxic T lymphocyte (CTL) responses and minimize off-target toxicity. Targeted modulation of type 1 conventional dendritic cells (cDC1s), a subset of DCs superior in antigen cross-presentation, in lymph nodes will enable optimal activation of CTL responses and result in robust immunotherapy, but has not been achieved so far. The primary goal of this project is to develop a macroscale materials-based system that integrates immune cell-homing macroporous materials with metabolic glycan labeling to achieve cDC1 recruitment, labeling, and targeting in vivo. With this material system, we aim to develop an unprecedented technology for targeted conjugation of immunomodulatory agents, including antigens, adjuvants, and cytokines, to cDC1s in lymph nodes, and further develop potent and safe cancer immunotherapy. To achieve this, an injectable macroporous biomaterial loaded with cDC1-recruiting chemokines and azido- sugars will be used to recruit and metabolically label cDC1s with chemical tags (e.g., azido group) in situ. These chemically tagged cDC1s can migrate from the biomaterial to lymph nodes for subsequent targeted conjugation of immunomodulatory agents via efficient and bioorthogonal click chemistry. Experiments will be organized around three aims. In Aim 1, injectable pore-forming alginate gels with independently tunable pore size, stiffness, viscosity, and chemokine release kinetics will be developed, and the impact of each parameter on the immune cell recruitment profile will be elucidated, in order to rationally design macroporous materials that can preferentially recruit and metabolically label cDC1s with azido groups in situ. In Aim 2, targeted delivery of tumor neoantigens and adjuvants or liposomal vaccines to azido-labeled cDC1s in lymph nodes via click chemistry will be explored, with a goal of improving neoantigen-specific CTL responses and the overall antitumor efficacy against poorly-immunogenic solid tumors. In Aim 3, targeted conjugation and surface display of immunomodulatory agents on cDC1s in lymph nodes will be explored to regulate cDC1-T cell interactions and amplify CTL responses. We hypothesize that cytokines, once conjugated, can be retained on cDC1 surface for hours to provide continuous stimulation to effector T cells during the T cell priming process. The completion of this project will lead to new immunotherapies with robust antitumor efficacy against solid tumors and reduced off-target side effects. Further, the cDC1 recruitment, labeling and targeting technology will also be promising for future development of therapies against autoimmune disorders and infectious diseases.