Using the IL-1R1 and its ligands to optimize the T cell immune response to cancer

IL-1α and β were discovered more than 50-years ago, and knowledge about these pleiotropic cytokines has grown exponentially since that time. Therapeutic use of these molecules has been limited by toxicity, and their blockade has had limited success in inflammatory disorders. In 2017, the CANTOS trial using canukinumab

and antibody to IL-1β, showed an unexpected association of blocking IL-1β and a dose dependant reduction in the incidence of cancers, rekindling interest in the role of IL-1’s molecules in tumor immunity. However, our data thus far suggests unappreciated complexity. We and others have shown that the of blocking IL-1β in

mouse models of cancer, and our published and preliminary data suggest that the mechanism by which anti- tumor immunity evolves is not straightforward. For example, blocking IL-1β permits immunostimulatory T cell activation by IL-1α to proceed unopposed, favoring tumor immunity. In parallel, blocking IL-1β’s effects on

myeloid cells modifies the tumor microenvironment independently to favor CD8 T cell mediated anti-cancer immunity. The immunotherapeutic effects of IL-1α appear to be operating through the CD8 T cell IL-1R1, and we propose that by understanding this pathway more completely, we can greatly enhance its activity.

Moreover, IL-1R1-driven effects on myeloid cells appear to inhibit anti-cancer immunity in the TME, and we hypothesize that understanding these effects will allow us to target this pathway with precision. To visualize these changes histopathologically, we have employed the powerful CyCIF platform. To test hypotheses in

vivo, we will use novel molecules known as AcTakines. These compounds target cytokine activity or blockade precisely to specific cell types in vivo without systemic toxicity and will help us to dissect these immune pathways in tumor-bearing animals. Because these drugs are being developed for future use in humans, our

work will serve as a basis for a better mechanistic understanding of their future use in cancer immunotherapy. We believe this is a new and unexplored pathway through which we can greatly enhance anti-tumor immunity, contributing fundamentally to immunotherapy of cancer.