Abstract 2700: Therapeutic IL-33 enhances the antigen presentation function of ILC2s to exert anti-tumor immune activity

Abstract IL-33 regulates the function of ILC2s through ST2. However, the role of IL-33, especially exogenous IL-33, on ILC2s in tumors is controversial depending on the cytokines they secrete. Here we report that exogenous, but not endogenous, IL-33 significantly inhibits the progression of a variety of mouse solid tumors, including melanoma, colorectal cancer, lung adenoma, and breast cancer. By inoculating tumor cells in Il1rl1−/- and NSG mice, we found that the tumor-suppressive effect of IL-33 on tumors was dependent on the expression of ST2 receptors and the presence of lymphocytes. Regarding tumor-infiltrating immune cells, exogenous IL-33 significantly increases the proportions of ST2+ Tregs (1. 10 ± 0. 20% vs. 1. 74 ± 0. 36%), eosinophils (6. 00 ± 1. 33% vs. 22. 73 ± 6. 51%), Granzyme B+ CD8+ T cells (4. 32 ± 2. 77% vs. 11. 53 ± 6. 81%), and bulk ILC2s (0. 08 ± 0. 04% vs. 5. 31 ± 1. 33%) and IA/IE+ ILC2s (0. 02 ± 0. 01% vs. 3. 67 ± 1. 03%). In draining lymph nodes, IL-33 also significantly increases the proportions of ILC2s (0. 03 ± 0. 02‰ vs. 6. 37 ± 1. 71‰) and IA/IE+ ILC2s (0. 003 ± 0. 003‰ vs. 4. 38 ± 1. 21‰). Importantly, single-cell transcriptomic analysis on tumor-infiltrating ILC2s highlights the expression of genes related with antigen processing and presentation including H2-K1, H2-Q7, B2m, Hspa1a, Hspa1b, Creb1, Hspa4, Tap1 and Tap2. We testified this finding by DQ-OVA experiment and found that IL-33 could promote ILC2s to up-take and process exogenous antigens (17. 78 ± 0. 75 fold vs. 22. 02 ± 0. 75 fold). The antigen presentation function of ILC2s was further established by mixed lymphocyte culture where BALB/c ILC2s potently stimulated C57BL/6 CD8+ T cell proliferation, which was further augmented by IL-33 treatment. Taken together, our data demonstrate an anti-tumor function of therapeutic IL-33 that elevates the number and antigen presentation function of ILC2s. Citation Format: Jie Liu, Zhenchu Feng, Hongyan Wei, Chang Li, Xiaoshi Li, Wenlong Chen, Yixi Ke, Minjun Wang, Lantian Liu, Cunni Zheng, Quan Liu. Therapeutic IL-33 enhances the antigen presentation function of ILC2s to exert anti-tumor immune activity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2700.