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

Young female patients with cancer are likely to become sub-fertile or infertile even if they ultimately overcome cancer through various therapies. Cancer immunotherapy has recently emerged as a promising novel therapy against cancers with high malignancy and lethality, but it is unclear whether cancer immunotherapy affects female fertility. This study employed MCA205 cell-allotransplanted B6 mice as a model to investigate whether two popular immunotherapies—PD-1 monoclonal antibody (PD-1) therapy and whole cancer cell vaccine (WCV) therapy—affect ovarian function. MCA205 allotransplanted (M) mice exhibited decreased follicle numbers at each stage, decreased proliferation, increased apoptosis, and a decreased oocyte maturation rate. WCV treatment significantly reversed these abnormalities, whereas PD-1 did not. RNA sequencing of the ovaries revealed that multiple differentially expressed genes (DEGs) were involved in inflammation pathways. Furthermore, cytokine microarray characterized CXCL10 with both biggest increment in M group and best rescue in WCV group. Next, CXCL10 antibody Immunoprecipitation in ovarian lysate and liquid chromatography-mass spectrometry (LC-MS) baited the only receptor IL18R1. Furthermore, we found that CXCL10 impaired ovarian function through three pathways: inducing ovarian fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, promoting primordial follicle overactivation through CXCL10→IL18R1→p-AKT, and increasing ovarian inflammation through CXCL10→IL18R1→p-P65. Finally, we rescued the decreased ovarian function in the M group by blocking the CXCL10→IL18R1 pathway with CXCL10 antibody or a CXCL10–IL18R1 interface peptide, CIBB. This study provides mechanical evidence and translational strategies for WCVs to achieve the dual functions of suppressing tumor progression while protecting ovarian function.