Synthetic Ligands for Directing Immune Responses

Abstract: The human immune system can combat various antigens—from natural to unnatural entities. This plasticity is the immune system's strength. Still, some target antigens fail to produce a desired immune response, either because they do not elicit the desired T cell response (e.g., Th1, Th2, or Th17) or because they fail to elicit robust immune signaling. This project aims to generate and investigate antigens that can deliver combinatorial signals. Our strategy is to use chemical probes to supply the tailored signals. Aim 1 draws on our previous results showing that antigens that can bind the dendritic cell (DC) lectin DC-SIGN and the toll-like receptor 7 (TLR7) elicit a potent Th1 response. This outcome is distinct from that of an untargeted antigen equipped with a TLR7 agonist or an antigen lacking the TLR agonist but targeted to DC-SIGN. Harnessing this response in a mouse tumor model provides robust antitumor activity. We now propose to compare the signaling and immune responses of other TLR-lectin combinations by fashioning antigens that can combinatorially engage target receptors (Aim 1). Effective combinations will be assessed in vivo and compared to signals from our previous conjugate (Aim 3). In Aim 2, we shall evaluate an alternative strategy to augment immunity, which involves exploiting the flexibility of the T cell receptor. Studies of allergic reactions to covalent drugs (e.g., penicillins) indicate that peptides bearing residues beyond those found in the canonical 20 amino acids can be presented on major histocompatibility complexes (MHCs) and recognized by the T cell receptor. We postulate that antigens that can elicit responses from the B cell and T cell receptors will lead to robust immune responses. To this end, we propose to develop a synthetic platform to explore and harness T cell receptor plasticity to augment immune responses to poorly immunogenic species, such as glycans. We anticipate that the results from these studies will yield new strategies to recruit the immune system to treat human disease.