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

Abstract

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(6_Suppl):Abstract nr 2700.