Study of the IL-33-driven immune cell organization underpinning responses to immune checkpoint blockade cancer therapy

The immune checkpoint blockade cancer therapy (ICB) can greatly prolong survival in responders. However, significant improvement of the response rate of ICB is in urgent need. We have found that IL33 is expressed in normal epithelial cells of lining tissues such as lung and skin but drastically down-regulated in high- grade tumor cells in multiple human carcinomas. These clinical data support the notion that down-regulation of IL33 is a major mechanism of tumor immune evasion. How IL-33 contributes to responses to current ICB therapy is not explored. Interestingly, our bioinformatics analysis revealed that the IL33 receptor ST2 mRNA is upregulated in human tumor tissues after successful PD-1 blockade treatment. Using mouse models, we showed that the IL33/ST2 signaling was required for therapeutic effect of ICB therapy. In addition, we demonstrated that IL33 was highly induced in immunogenic murine tumor cells during ICB tumor therapy and tumor-expressed IL33 was required for responses to ICB therapy. Despite these strong evidence supporting an antitumor function of both endogenous and administered IL33, the underlying molecular and cellular mechanisms are not well understood. Our preliminary data showed that ICB-induced tumor-expressed IL33 drove conspicuous immune cell re-organization in the tumor microenvironment (TME). We further demonstrated that the antitumor effect of IL33 is dependent on DC1 and CD8+ T cells, suggesting their role in anchoring the antitumor effect of IL33. Interestingly, IL33 also led to accumulation of ST2+ Treg cells in the TME, which might counteract the antitumor effect of IL33 and maintain an immune equilibrium. We hypothesize that tumor-derived IL33 underpins responses to ICB tumor immunotherapy through promoting a drastic reorganization of the immune cellular network in the TME. SA1 Determine how IL33 expression is induced in tumor cells by ICB tumor therapy. SA2. We will define how IL33 organizes the immune cellular network that mediates responses to ICB tumor therapy. SA3. Determine the mechanisms how ST2 signaling in regulatory T cells (Tregs) limits antitumor activities of IL33.