Type 2 innate lymphoid cells play a diverse role in breast cancer development and progression 2258430

Abstract

Abstract Introduction The tumor microenvironment (TME) is a crucial regulator of breast cancer (BC) development. It comprises acellular and cellular factors, including immune cells like type 2 innate lymphoid cells (ILC2s). We aim to understand the role of ILC2s in the BC TME and whether they can be therapeutically targeted. Methods To reveal the ILC2 phenotype in BC, we used the polyoma middle T antigen transgenic mouse model, which mimics luminal BC development. Results Single-cell (sc)RNA sequencing and flow cytometry experiments showed that ILC2s (expressing Gata3, Rora, Il2ra, and Il7ra) accumulated in the mammary fat pad (MFP) during BC development, and ILC2s phenotypically changed during tumor development by increasing PD-1 and Neuropilin-1 expression. Next, we tested if ILC2s directly regulate cancer cell growth in vitro. Co-culturing the BC cell line ‘VO’ with healthy MFP or tumor ILC2s for 48 hours increased the number of viable VO cells. To assess the functional relevance of ILC2s in BC in vivo, we co-injected ILC2s and VO cells orthotopically into FVB mice and measured the tumor growth. While 85% of the mice co-injected with VO cells and ILC2s developed a tumor, 50% of the VO-only recipients rejected the tumor cells. ILC2 co-injection increased infiltration of Gr-1+CD11b+ neutrophils, which could inhibit anti-cancer immunity. Injecting the breast cancer cell line ‘Py8119’ into the healthy MFP of control and ILC2-deficient mice resulted in similar findings, with smaller tumors in mice lacking ILC2s. Conversely, when we injected the ILC2-activator IL-33 into Py8119 tumor-bearing mice, the tumors shrank massively and were full of ILC2s. These results indicate distinct ILC2 states, making ILC2s context-dependent, either pro- or anti-tumorigenic. Conclusion We showed that ILC2s accumulate, undergo phenotypic changes, and promote an immunoinhibitory environment during BC development. Notably, we can modify the ILC2 phenotype, making them anti-tumorigenic and a promising target for new therapeutic approaches. Funding Source Hewitt Foundation for Biomedical Research Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)