Background: Ovarian cancer remains the most lethal gynecological cancer among women in Canada. Recent advances in immunotherapies, such as checkpoint blockade, prove limited success in preclinical models and clinical trials of ovarian cancer. Thus, developing new therapeutic strategies that synergizes with checkpoint blockade is a clinical priority.

Group 2 innate lymphoid cells (ILC2s) are tissue resident cells that are uniquely poised to sense and integrate inflammatory signals, and during malignant transformation, direct anti-tumor immunity in its early stages. Recently, we identified the presence of ILC2s in the murine ovary that respond to IL-33 which, in turn, induces the expression of PD-1 on these cells. Thus, we hypothesize that IL-33 sensitization of ovarian tumors enhances the effects of anti-PD-1 therapy by potentiating ILC2 and T-cell anti-tumor activity.

Methodology: Female C57Bl/6 mice were surgically implanted with ID8Trp53-/-Brca1-/- syngeneic cells to form orthotopic ovarian cancer tumors. Mice were subsequently treated with intraperitoneal injections of 500ng rIL-33 for 7 days, then every 2 days thereafter and/or 250ug anti-PD-1 every day for a total of 5 injections.

Results: Treatment of IL-33 or anti-PD-1 alone yielded a modest effect on survival (median survival 68d. vs. 69d. respectively) compared to vehicle control (median survival 63d.). However, the combination of IL-33 and anti-PD-1 provided a synergistic effect to substantially delay mouse mortality (median survival 83d.), with 2/8 mice found to be tumor-free post-mortem analysis. Furthermore, in our tumor immune-profiling analysis we found increased number and activation of ILC2s and T cells in response to IL-33 and anti-PD-1 combination therapy.

Conclusions: Our data suggests that IL-33 and anti-PD-1 therapy synergistically enhances anti-tumor immunity and therapeutic efficacy in an orthotopic model of ovarian cancer.