Oophorectomy significantly impacts response to immune therapy regimens in preclinical models of ovarian cancer

Abstract

<h3>Objectives:</h3> We have previously shown that PARP inhibition (PARPi) synergizes with CTLA-4 immune checkpoint blockade, improving survival in syngeneic high grade serous ovarian cancer models. This combination is currently being tested in clinical trials (NCT02571725 and NCT04034927). In the same models, no therapeutic benefit was seen when PARPi was combined with PD-1 blockade. We attribute the selective synergy of CTLA-4 antibody with PARPi to changes in the ovarian tumor microenvironment (TME). An increase in IFNγ production as a result of treatment with PARPi/CTLA-4 antibody was a predictor of improved survival. These results illustrate the importance of establishing cancer models that accurately represent conditions in the ovarian TME. Most preclinical studies are conducted in mice with intact ovarian function, while women with ovarian cancer are postmenopausal or undergo oophorectomy as part of their treatment. Immunotherapy clinical trials have observed differences in outcomes based on sex. Emerging evidence shows that estrogen affects immune function. Therefore, we tested the impact of oophorectomy on the immune microenvironment and its effects on disease outcome. <h3>Methods:</h3> Oophorectomy was performed on five-week-old female FVB mice that were subsequently injected intraperitoneally with BR5-Akt high grade serous ovarian cancer cells. Three days after tumor challenge, mice received a PARP inhibitor (ABT-888) and immune checkpoint inhibitor (anti-PD1 antibody or CTLA-4 antibody). Mice that had undergone laparotomy without oophorectomy (sham) or no surgery served as controls. On day 24, peritoneal T cells were analyzed by flow cytometry for phenotype and IFNγ production. Tumor burden was measured by non-invasive bioluminescence imaging. <h3>Results:</h3> Estrogen depletion through oophorectomy affects T cell phenotypes, increasing the proportion of central memory CD8 T cells compared to controls in the anti-PD1 combination treatment group. In the same group, estrogen depletion is associated with an increase in IFNγ production by both CD4 and CD8 T cells. These changes were associated with a decrease in tumor burden. The same effects were not seen in mice treated with combination PARPi and CTLA-4 antibody. <h3>Conclusions:</h3> The data presented here confirm that estrogen impacts tumor associated lymphocyte phenotype and function, affecting parameters that are associated with improved disease outcomes in combination of PARPi and immune checkpoint blockade. With knowledge of the significant impact of estrogen on anti-tumor immune function, we can develop pre-clinical models that accurately reflect the immune microenvironment established in ovarian cancer. This will facilitate the development of highly effective immunotherapeutic regimens that will enhance their translational potential and ultimately improve patient outcomes.