CXCL10 and CCL5 as feasible Biomarkers for Immunotherapy of Homologous Recombination Deficient Ovarian Cancer

Ovarian cancer is the most common gynecological malignancy, in which about 50% of patients have homologous recombination defects (HRD). Although PARP inhibitors can improve the survival benefit of patients, some patients eventually present with disease progression and require comprehensive treatment in combination with multiple lines of drugs such as immunotherapy. Therefore, this study aimed to explore biomarkers to guide immunotherapy in ovarian cancer with HRD to guide clinical practice.We found that CXCL10, a major downstream target gene of the cGAS-STING pathway, and CCL5, which acts synergistically with CXCL10, were associated with HRD, and patients with high expression of CXCL10 and CCL5 had survival. Immunohistochemical results confirmed that CXCL10 and CCL5 were highly expressed in HRD-positive ovarian cancer. Single-cell sequencing and tumor mutation data suggested that CXCL10 and CCL5 in the tumor microenvironment were mainly derived from immune cells  rather than gene mutations. In addition, we found that CXCL10 and CCL5 high expression samples had higher stromal cell scores as well as immune cell scores, predicting lower tumor purity in the samples. Further analysis showed that CXCL10 and CCL5 expression were associated with common immune checkpoint-related genes (PD-1/PD-L1/CTLA4), and the combined predictive efficacy of CXCL10 and CCL5 was significantly higher than that of PD-1 in predicting the effect of anti-PD-1 immunotherapy, and the effect of CXCL10 and CCL5 on survival was statistically different in multivariate Cox regression. In summary, CXCL10 and CCL5 may become new biomarkers to guide immunotherapy in homologous recombination-deficient ovarian cancer.