The role of decoy receptor IL-1R2 in Treg biology and anti-tumor immunity

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Project Summary/Abstract Interleukin-1B (IL-1B) is a pro-inflammatory cytokine with conflicting roles in mouse and human cancers. The cytokine enhances tumor growth by promoting angiogenesis, and chronic inflammation mediated by IL-1B can induce carcinogenesis. At the same time, IL-1 signaling bolsters the adaptive immune system, polarizing CD4+ T cells toward T helper type 1 and 17 lineages and enhancing the effector function of CD8+ T cells to improve tumor cell killing. A large clinical trial found that anti-IL-1B treatment significantly reduced tumor incidence in humans, highlighting the effect of IL-1 signaling on human health. IL-1 signaling is well-regulated by both a receptor antagonist (IL-1RA) and a non-signaling decoy receptor (IL-1R2). IL-1RA acts at the organism level to suppress systemic inflammation, while IL-1R2 is thought to attenuate local inflammation in tissues. Using RNA sequencing, we have identified a population of highly activated IL-1R2+ regulatory T cells (Tregs) in healthy skin and tumor samples from mice and humans. Tregs are critical suppressors of inflammation in tissues, but tumor infiltrating Tregs can dampen adaptive immunity to promote cancer growth. However, the function of IL-1R2 in cancer and Treg biology is not well understood. In our hands, deleting IL-1R2 on Tregs led to increased tumor growth in mice, suggesting that IL-1 signaling enhances Treg activation. This proposal will test whether Treg expression of IL-1R2 attenuates their activation in a cell intrinsic fashion by neutralizing local IL-1B. First, we will define the factors that induce IL-1R2 expression on Tregs in mice and humans (Aim 1). We will then investigate the functional role of IL-1R2 on tumor infiltrating Tregs (Aim 2). Lastly, we will determine whether IL-1R2 can be used as a target to selectively deplete Tregs in tumors and bolster anti-tumor immunity (Aim 3). The proposal will not only broaden our understanding of IL-1 signaling in Tregs but may also establish a new approach for cancer immunotherapy. This research strategy will be conducted alongside a comprehensive training plan to develop the applicant’s career as an academic physician-scientist. Training will include structured and rigorous mentorship in technical skills and experimental design from a highly qualified physician-scientist sponsor, carried out through regular one-on-one and lab meetings, courses, seminars, journal clubs, and immunology department events. The research and training will take place at the University of California, San Francisco, which provides an excellent research environment for immunology alongside an outstanding graduate education in biomedical sciences.