Group 2 Innate Lymphoid Cells in Ovarian Health and Disease

Abstract

Group 2 innate lymphoid cells (ILC2s) are a subset of tissue-resident lymphocytes that function as first responders to physiological tissue inflammation, and during malignant transformation, can direct tumor immunity in its early stages. How ILC2s contribute to ovarian health and whether they can be harnessed to improve anti-tumor therapy has not yet been elucidated. Herein, we identified the novel presence of ILC2s in the mouse ovary, and found that they represent a dynamic population that is regulated by hormonal signalling and epithelial-derived cytokines. Our data provides a phenotypic and functional characterization of ILC2s in the ovary during normal reproductive cycling, ovulation, and in a mouse model of polycystic ovarian syndrome.

Having identified ILC2s in the healthy cycling mouse ovary, we next sought to extend our studies to ovarian cancer, where the role of ILC2s is undefined. Herein, we report that IL-33 treatment increases ILC2 abundance, activation, and effector function in mouse ovarian tumors. IL-33-activated ILC2s upregulate surface expression of PD-1, providing a rationale to consider anti-PD-1 (αPD-1) immunotherapy in combination. Indeed, we found that IL-33+αPD-1 treatment significantly improves survival in mice bearing ovarian tumors compared to either monotherapy. IL-33 treatment enriches ILC2s in the tumor microenvironment where they exhibit enhanced cytotoxic capabilities and expression of effector molecules IL-5 and IL-13. Survival analyses revealed that IL-5, but not IL-13 is dispensable for the therapeutic efficacy of IL-33+αPD-1 treatment. Beyond ILC2s, T cells, B cells, and NK cells all contribute to the therapeutic effect of IL-33+αPD-1 unveiling a model in which this combination treatment exerts its effects through multiple immune pathways. Together these data position ILC2s as key mediators of ovarian homeostasis and disease.