Whole Cancer Cell Vaccine Protects Ovarian Functions in Tumor-bearing Mice through Downregulating CXCL10

Your female patients with cancer will probably become sub-fertile or infertile even though some finally overcome the cancer through various therapies. Cancer immunotherapy is recently emerging as a promising novel therapy against cancer with high malignancy and lethality, but whether or not cancer immunotherapy affect female fertility is rarely known. In the present study, we employed MCA205 cells-xenografted B6 mice as model to investigate whether two popular immunotherapies, PD-1 monoclonal antibody (PD-1) and whole cancer cell vaccine (WCA), affect ovarian function. We found that MCA205 xenograft (M) conduced to decreased follicle numbers at each stage, decreased proliferation and increased apoptosis, decreased oocyte maturation rate and disrupted estrus cycle. WCA treatment significantly rescues the upper abnormalities while PD-1 didn't. Ovary RNA sequencing revealed that multiple DEGs (differentially-expressed genes) are involved in inflammation pathways. Next, cytokine microarray characterized CXCL10 with both biggest increment in M group and best rescue in WCA group. Next, CXCL10 antibody Immunoprecipitation in ovarian lysate and LC-MS baited the only receptor IL18R1. Next, we found that CXCL10 could at least impaired ovarian function through three pathways: it can increase ovarian inflammation through CXCL10→IL18R1→p-P65, induce ovarian fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, and promote primordial follicle overactivation through CXCL10→IL18R1→p-AKT. Finally, we succeeded in rescuing ovarian function in M group through blocking the CXCL10→IL18R1 binding with CXCL10 antibody or a CXCL10-IL18R1 interface peptide. This study provided both mechanical evidences and translational strategies for whole cell vaccine in achieving dual functions, suppressing tumor progression meanwhile protecting ovarian function.