Han Yue, Guo Zhewei, Jiang Lijuan, Li Xinyue, Chen Jiahui, Ouyang Ling, Li Yan, Wang Xiaoying
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University Shenyang, Liaoning, China.
Am J Cancer Res. 2023 May 15;13(5):1904-1922. eCollection 2023.
This study aims to identify biomarkers of ovarian cancer, specifically those tumors exhibiting homologous recombination deficiency (HRD), to contribute to the optimization of immunotherapy. We screened the differentially expressed genes coding for CXCL10 and CCL5 by analyzing the transcriptome data of patient with different HRD scores in the ovarian cancer cohort of the TCGA database and validated our results using pathological tissue sections. The cellular origin of CXCL10 and CCL5 were identified using the single-cell sequencing data extracted from the GEO database combined with the tumor mutational burden (TMB) and single nucleotide polymorphism (SNP) data obtained from the TCGA database. We found that CXCL10 and CCL5 expression levels were correlated with HRD score. Analysis of single-cell sequencing results and tumor mutation data suggested that both CXCL10 and CCL5 present in the tumor microenvironment were primarily derived from immune cells. In addition, we found that samples with high expression of CXCL10 and CCL5 also had higher stromal cell and immune cell scores, indicating low tumor homogeny. Further analysis showed that CXCL10 and CCL5 expression was associated with immune checkpoint-related genes, and the efficacy of using these proteins as biomarkers was significantly higher than that of PD-1 in predicting the effect of anti-PD-1 immunotherapy. The expression of CXCL10 and CCL5 had statistically different effects on the survival of patients, based on multivariate Cox regression. In summary, the results demonstrate that in ovarian cancer, the expression of CXCL10 and CCL5 are correlated with HRD. When CXCL10 and CCL5 are secreted by immune cells, immune cell infiltration can be chemotactic and predict the effect of immunotherapy more efficiently than using PD-1 as a biomarker. Therefore, CXCL10 and CCL5 look to be promising novel biomarkers to guide immunotherapy in ovarian cancer.
本研究旨在识别卵巢癌的生物标志物，特别是那些表现出同源重组缺陷（HRD）的肿瘤，以促进免疫治疗的优化。我们通过分析TCGA数据库卵巢癌队列中不同HRD评分患者的转录组数据，筛选出编码CXCL10和CCL5的差异表达基因，并使用病理组织切片验证了我们的结果。利用从GEO数据库提取的单细胞测序数据，结合从TCGA数据库获得的肿瘤突变负荷（TMB）和单核苷酸多态性（SNP）数据，确定了CXCL10和CCL5的细胞来源。我们发现CXCL10和CCL5的表达水平与HRD评分相关。对单细胞测序结果和肿瘤突变数据的分析表明，肿瘤微环境中存在的CXCL10和CCL5主要来源于免疫细胞。此外，我们发现CXCL10和CCL5高表达的样本也具有更高的基质细胞和免疫细胞评分，表明肿瘤同质性较低。进一步分析表明，CXCL10和CCL5的表达与免疫检查点相关基因有关，在预测抗PD-1免疫治疗效果方面，使用这些蛋白作为生物标志物的效能显著高于PD-1。基于多变量Cox回归分析，CXCL10和CCL5的表达对患者生存有统计学上的不同影响。总之，结果表明在卵巢癌中，CXCL10和CCL5的表达与HRD相关。当CXCL10和CCL5由免疫细胞分泌时，免疫细胞浸润具有趋化作用，并且比使用PD-1作为生物标志物更能有效地预测免疫治疗效果。因此，CXCL10和CCL5有望成为指导卵巢癌免疫治疗的新型生物标志物。
