Type 2 innate lymphoid cells fuel breast cancer development via direct interactions with cancer cells and by inhibiting anti-cancer immunity 4454

Abstract Description The tumor microenvironment is an important regulator of breast cancer (BC) development. It comprises acellular and cellular factors, including immune cells like type 2 innate lymphoid cells (ILC2s). The exact molecular mechanisms of how ILC2s regulate BC immunity remain largely unknown. To analyze BC ILC2s, we used the polyoma middle T antigen transgenic mouse model, mimicking luminal BC development. Single-cell (sc)RNA sequencing and flow cytometry experiments showed that during BC development, ILC2s accumulated in the mammary fat pad (MFP) and phenotypically changed by upregulating PD-1 and Neuropilin-1 expression. To test if ILC2s directly regulate cancer cell growth, we co-cultured the BC cell line ‘VO’ with ILC2s and detected increased numbers of viable VO cells. To test the function of ILC2s in BC in vivo, we orthotopically injected the BC cell line ‘Py8119’ into the MFP of control and ILC2-deficient mice. ILC2-deficient mice developed smaller tumors, with a lower frequency of intratumoral Gr-1+CD11b+ suppressor neutrophils, compared to control mice. Co-injecting VO cells with ILC2s into the MFP of healthy mice resulted in the opposite phenotype, with bigger tumors and larger Gr-1+CD11b+ numbers in co-injected mice compared to mice injected only with VO cells. In summary, we showed that ILC2s directly and indirectly fuel BC development. Further experiments will reveal if ILC2s can be used as targets to treat BC patients. Funding Sources George E Hewitt Foundation for Medical Research Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)