Abstract C034: Epithelial alarmins coordinate type 2 immunity in colorectal cancer

Abstract Type 2 (T2) immune responses, including the IL-4Ra cytokines IL-4 and IL-13, are induced in many cancers. T2 immunity can suppress anti-tumor responses and support progression, and therapeutic inhibition of IL-4Ra signaling combined with checkpoint blockade has shown promising effects in mouse tumor models and a small clinical trial for metastatic lung cancer. Despite these advances, very little is understood about how T2 responses are activated in cancer, or how T2 cells and molecules shape the tumor microenvironment. We sought to investigate the role and regulation of T2 immunity in colorectal cancer (CRC), the second-leading cause of cancer death worldwide. Using spontaneous mouse tumor models and publicly available human scRNA-seq data, we find that CRC tumors establish a T2-polarized microenvironment through specific induction of IL-13, leading to IL-4Ra-mediated remodeling of the myeloid and epithelial compartments. Unexpectedly, mast cells (MC) were the dominant source of tumor-associated IL-13 in mouse and human mismatch repair-proficient (MMRp) tumors, which represent >85% of CRC and are unresponsive to current immunotherapies, while group 2 innate lymphoid cells (ILC2) were identified as a second IL-13+ population in mouse intestinal tumors. Furthermore, we show that these two arms of tumor-associated T2 immunity are controlled by distinct epithelial-derived signals. On one hand, tumor MC activation required IL-33, which was upregulated by tumor epithelial cells and signaled through MC-intrinsic ST2. However, rIL-33 administration was not sufficient to activate MC in vivo, suggesting a requirement for additional signal(s). Correspondingly, IL-13+ MC intercalated among the tumor epithelium and upregulated CD103, and antibody blockade of CD103 blunted MC activity. These data suggest that tumor epithelial cells activate MC via soluble (IL-33) and contact-dependent (CD103) signals. In parallel, ILC2 activation required both MC activity and IL-25+ tuft cells, the latter of which expanded in the peritumoral environment in an IL-13-dependent manner. Disruption of the IL-33/ST2-MC axis blunted tumor T2 polarization, while hyperactivation of the tuft-ILC2 circuit boosted T2 polarization. Ongoing work seeks to evaluate the impact of T2 immunity on anti-tumor responses and immunotherapy in malignant/metastatic CRC. Citation Format: Thornton W. Thompson, Shealyn O'Connor, Debarati Bhadury, Tyler Billipp, Jakob von Moltke. Epithelial alarmins coordinate type 2 immunity in colorectal cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C034.