Predictive Value Of CXCL10 And CCL5 In Immunotherapy Of HRD Positive Epithelial Ovarian Cancer

Objective: Epithelial ovarian cancer is the most common gynecological malignancy,in which about 50% of patients have homologous recombination defects(HRD).Although targeted drugs 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 epithelial ovarian cancer with HRD.Methods: In this study,the HRD scores of different patients in the ovarian cancer cohort in the TCGA database were analyzed,and the transcriptome data of the top20% and the bottom 20% of the HRD scores were analyzed,and the differentially expressed genes CXCL10 and CCL5 were screened.The differential expression of CXCL10 and CCL5 proteins in pathological tissue sections was verified in the offline cohort.The relationship between CXCL10 and CCL5 and gene mutation in tumor microenvironment was determined based on tumor mutation burden data in the TCGA database.The expression characteristics of CXCL10 and CCL5 were analyzed in relation to tumor microenvironment and immune-related features,and their predictive value was verified in the IMvigor210 immunotherapy cohort.Results: It was found that CXCL10 and CCL5,the main downstream target genes of cGAS-STING pathway,were correlated with the status of HRD.Patients with high expression of CXCL10 and CCL5 had longer survival.After treatment with PARP inhibitors,expressions of CXCL10 and CCL5 were significantly increased.Analysis of tumor mutation load data suggested that the high expression of CXCL10 and CCL5 in tumor microenvironment was not gene mutation.In addition,it was found that samples with high expression of CXCL10 and CCL5 had higher stromal cell scores and immune cell scores,indicating lower tumor purity.Further analysis showed that CXCL10 and CCL5 expression were correlated with common immune checkpoint related genes(PD-1/PD-L1/CTLA4),and in predicting the effect of anti-PD-1immunotherapy,The combined predictive efficacy of CXCL10 and CCL5 was higher than that of PD-1,and the influence of CXCL10 and CCL5 on patients’ survival was statistically different in multivariate COX regression.Conclusion: In conclusion,the current study results prove that CXCL10 and CCL5 are highly expressed in HRD positive epithelial ovarian cancer and are correlated with patient survival.The high expression of CXCL10 and CCL5 is related to the formation of immune features such as the infiltration of immune cells in the tumor microenvironment.In addition,according to the current analysis,compared with PD-1,CXCL10 combined with CCL5 has higher efficacy in predicting immunotherapy efficacy and can replace PD-1 in predicting immunotherapy efficacy.Therefore,CXCL10 and CCL5 are expected to be new biomarkers to guide immunotherapy in homologous recombinant defective epithelial ovarian cancer,which still need to be confirmed by more extensive studies in the future.