Blocking the CXCL10-IL18R1 Axis Protects Ovaries from Tumor-induced Damage

The ovary is susceptible to harmful environmental factors (hEFs). Tumor invasion is an intracorporal hEF. However, it is unclear whether and how tumor invasion compromises ovarian function, making it challenging to target and prevent this harm prior to diagnosis and cancer treatment. To develop a targeted therapy to protect ovarian function during tumor invasion, we used MCA205 (mouse fibrosarcoma) cell-allotransplanted B6 mice as a basic model (M group), and two popular therapeutic models—PD-1 monoclonal antibody injection in allotransplanted B6 mice (PD-1 group) and whole cancer cell vaccine (WCV) injection in allotransplanted B6 mice (WCV group)—to facilitate the discovery process. As expected, tumor infiltration in the M group reduced ovarian function in multiple ways. Interestingly, WCV injection strongly restored these anomalies, whereas PD-1 did not. Next, plasma cytokine microarrays revealed that the level of CXCL10 increased in the M group and was the best rescue in the WCV group. Next, we baited the sole CXCL10 receptor found in the ovaries, IL18R1. CXCL10 impairs ovarian function via three pathways: generating fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, encouraging primordial follicle overactivation through CXCL10→IL18R1→p-AKT, and increasing ovarian inflammation through CXCL10→IL18R1→p-P65. To improve ovarian function in the M group, we blocked the CXCL10→IL18R1 pathway with CXCL10 antibody or CIBB, an interface peptide. This study provides mechanical evidence and translational evidence for how tumor invasion compromises ovaries functioning and how to target and protect ovaries during tumor invasion.
Supplementary dataset 1
Related to Fig. 3A and 3B. This file includes two sheets. “All_samples-fpkm” includes FPKM values of all identified genes in ovaries from the CTR, M, VM, and PM groups (three repeats per group); “heatmap” includes all average log2 values (from three repeats per group) of 435 DEGs (differentially expressed genes) at the threshold of |log2(M/CTR)| ≥ 1.
Supplementary dataset 2
Related to Fig. 3C. This file includes 33 sheets. “Summary” includes all conc. Values (pg/mL) of 31 plasma DECs (differentially expressed cytokines); “Curves” include standard curves for all 31 cytokines; each of the other 31 sheets includes detailed assays for each plasma cytokine for the CTR, M, VM, and PM groups (five repeats per group).
Supplementary dataset 3
Related to Fig. 5A. This file includes two sheets. “peptides” includes all related values of all identified peptides; “Protein Groups” includes the related info. All the proteins corresponded to the identified peptides.