Non-reproductive tumor progression impairs ovarian function through CXCL10–IL18R1 axis

Abstract The ovary is susceptible to harmful environmental factors. Tumor progression (TP) is an intracorporal harmful environmental factor. It is known that TP could impair adjacent tissues through pro-inflammatory cytokines. However, it is unclear whether and how non-reproductive tumor progression (NRTP) impairs ovarian function. In this study, we used MCA205 (mouse fibrosarcoma) cell-allotransplanted B6 mice as a basic model (M group); meanwhile, we established two popular therapeutic models — PD-1 monoclonal antibody injection in allotransplanted mice (PD-1 group) and whole cancer cell vaccine (WCV) injection in allotransplanted mice (WCV group) — to facilitate the discovery process. As expected, TP in M group decreased ovarian function multifacetedly. Interestingly, WCV injection significantly reversed these abnormalities, whereas PD-1 did not. Next, plasma cytokine microarray characterized CXCL10 with both the biggest increment in M group and best rescue in WCV group. Next, we baited the only CXCL10 receptor, IL18R1, within ovaries. Next, we found that CXCL10 directly bound to IL18R1 to impair ovarian function through three pathways: inducing ovarian fibrosis through p-JNK→p-JUN → COL1A1, promoting primordial follicle overactivation through p-AKT→p-FOXO3A, and increasing ovarian inflammation through p-P65 → IFNγ. We have also preliminarily verified the CXCL10–IL18R1 axis and the upper three downstream pathways in MC38 (mouse colon cancer cells)-allotransplanted and B16F10 (mouse melanoma cells)-allotransplanted B6 mice. 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 of how NRTP impairs ovarian functions and how to target-protect ovaries under NRTP.