Type 2 innate lymphoid cells fuel breast cancer development by inhibiting anti-cancer immunity

Abstract

Abstract The tumor microenvironment is a crucial regulator of breast cancer (BC) development. It is composed of acellular and cellular factors, among others immune cells like type 2 innate lymphoid cells (ILC2s). The molecular mechanisms of how ILC2s regulate BC immunity remain largely unknown. To reveal the phenotype of ILC2s in BC, we used the polyoma middle T antigen transgenic mouse model, mimicking luminal BC development. ScRNA sequencing and flow cytometry experiments showed that ILC2s (expressing Gata3, Rora, Il2ra, and Il7ra) accumulated during disease development and that the ST2, cKit, and Neuropilin-1 expression on ILC2s increased with tumor burden. Additionally, PMA/Ionomycin restimulated ILC2s expressed stable interleukin-5 and -13 levels. We detected the same ILC2 phenotype in the tumors of BRCA1mutp53-/- mice, which mimic the basal BC subtype. To assess the functional relevance of ILC2s in BC, we co-injected ILC2s and the BC cell line VO orthotopically into FVB mice and measured the tumor growth. While 85% of the mice that were co-injected with VO cells and ILC2s developed a tumor, 50% of the VO-only recipients rejected the tumor cells. ILC2-co-injection induced an increased infiltration of Gr-1+CD11b+ neutrophils, which could potentially inhibit anti-cancer immunity. In summary, we show that ILC2s accumulate, get activated, and promote an immune-inhibitory environment. Further experiments will reveal if ILC2s can be used as targets to treat BC patients.