UCSF

Interleukin-1 (IL-1) is a pleotropic cytokine with complex biology. Because of its potent pro-inflammatory properties, several mechanisms have evolved to regulate its systemic and local effects. At the tissue level, a non-signaling decoy receptor, Interleukin-1 receptor 2 (IL-1R2) plays a major role in attenuating IL-1 mediated signaling. IL-1R2 is highly expressed on regulatory T cells (Tregs) that infiltrate both mouse and human tumors. Tregs respond to cytokines in their local environment to modulate their activity. IL-1 signaling is thought to regulate Treg effector function in the context of Type 1 and Type 17 inflammation and has primarily been characterized in autoimmune diseases. However, the function of IL-1 in tumor Treg biology is relatively unknown. Here, we show that a subset of highly activated Tregs induce IL-1R2 expression upon migration into tumors. In contrast to myeloid cells, induction of IL-1R2 on Tregs was mediated by T cell receptor (TCR) engagement and not IL-1-mediated signaling. Signaling through the canonical IL-1 receptor (IL-1R1) activated Tregs to express a unique gene expression signature and IL-1R2 potently attenuated this activation module in tumors. Accordingly, deletion of IL-1R2 on Tregs resulted in a more suppressive tumor microenvironment and increased tumor growth. In translational studies, we developed a novel IL-1R2 depleting antibody which was highly selective for tumor infiltrating Tregs. Tumor Treg depletion using this approach potently inhibited tumor growth without generating systemic autoimmunity. Taken together, we define the biology of IL-1R2 expression on tumor Tregs and provide the foundation for a novel therapeutic strategy to augment anti-tumor immunity.