Epithelial alarmin networks promote innate type 2 immune suppressive microenvironments in colorectal cancer 2608

Abstract Description Solid tumors establish microenvironments that support progression and impair anti-tumor immunity. IL-4/IL-13-driven “type 2” immune responses, typically associated with parasitic infections and allergy, are mobilized by tumors to polarize suppressive myeloid cells and promote malignancy. Accordingly, the antibody therapeutic dupilumab (blocks IL-4Ra) has shown promise in early clinical trials for lung cancer. We sought to understand how epithelial tumors activate type 2 immunity in mucosal tissue using the ApcMin/+ model of pre-malignant intestinal tumorigenesis. ApcMin/+ tumors established an innate type 2-polarized microenvironment characterized by IL-13/IL4Ra-dependent Arg1+ macrophage accumulation, tuft cell hyperplasia, and reduced IFNg responses. Tumor-associated ILC2 and intraepithelial mast cells (MC) were identified as the sources of IL-13. ILC2 activation required chemosensing by IL-25-producing tuft cells, whereas MC accumulation and activation required IL-33 signaling, which was upregulated by non-tuft tumor cells. Boosting of tumor-associated tuft cell activation further increased ILC2 IL-13 and Arg1+ macrophage polarization, while ST2 deficiency abrogated MC responses and enhanced anti-tumor Th1 cells. Publicly available human colorectal cancer scRNA-seq datasets revealed tumor-associated MC upregulation of IL-13, ST2, and IL17Rb. Thus, induction of parallel epithelial alarmin networks drives innate type 2 suppressive microenvironments in CRC. Funding Sources Supported by a postdoctoral fellowship from the Cancer Research Institute (TT) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)