宫颈癌中肿瘤免疫细胞浸润模式及预后价值

The infiltration pattern and the prognostic value of the tumor-infiltrating immune cells in cervical cancer

目的探讨宫颈癌中免疫细胞的浸润模式及预后价值。方法对肿瘤与癌症基因组图谱(TCGA)309例宫颈癌肿瘤样本的基因表达谱进行分析,通过CIBERSORT计算22种免疫细胞类型的比例。Cox回归模型分析浸润免疫细胞及免疫检查点分子基因表达与预后的关系。结果宫颈癌肿瘤组织中巨噬细胞、γδT细胞、活化的CD4^+记忆性T细胞、滤泡辅助性T细胞、浆细胞,未活化的肥大细胞比较丰富。高水平CD8^+ T细胞,活化的CD4^+记忆性T细胞及未活化的肥大细胞与较高总生存率相关(P<0.05),而高水平未活化的CD4^+记忆性T细胞及活化的肥大细胞与较低总生存率相关(P<0.05)。活化的CD4^+记忆性T细胞及活化的肥大细胞为宫颈癌患者生存的独立预后因素(P<0.05)。免疫检查点分子基因表达(CD274,PDCD1,CTLA4,ICOS)与CD4^+记忆性T细胞浸润水平呈正相关(P<0.05),与活化的肥大细胞浸润水平呈负相关(P<0.05)。ICOS是宫颈癌患者生存的独立预后因素基因表达。结论肿瘤浸润免疫细胞在宫颈癌患者预后中具有重要作用,同时也为宫颈癌免疫治疗揭示了潜在的生物标志物和靶点。

Objective To investigate the infiltration pattern and the prognostic value of the tumor-infiltrating immune cell in cervical cancer. Methods Clinical information and gene expression profiles from TCGA-CESC(The Cancer Genome Altas-Cervical squamous cell carcinoma and endocervical adenocarcinoma) dataset were retrospectively collected. CIBERSORT was used to determine the proportions of 22 immune cell types of 309 tumors. Cox regression model was performed to evaluate the association of tumor-infiltrating immune cells and immune checkpoint modulators with overall survival(OS).Results Of the 22 cell types, Macrophages(29.1%), gamma delta T cells(12.3%), activated CD4^+ memory T cells(8.0%), follicular helper T cells(7.6%), plasma cells(6.7%) and inactivated mast cells(5.5%) were abundant in cervical cancer. Univariate analysis showed that high proportions of CD8^+ T cells, activated CD4^+ memory T cells and inactivated mast cells were associated with prolonged OS, while high proportions of inactivated CD4^+ memory T cells and activated mast cells were associated with poor OS. Multivariate analysis showed that activated CD4^+ memory T cells(P=0.001, HR 0.323, 95% CI 0.180-0.581) and activated mast cells(P=0.003, HR 2.433, 95% CI 1.350-4.387) were independent prognostic factors for survival of patients with cervical cancer. The mRNA expression levels of Immune checkpoint molecular(CD274, PDCD1, CTLA4, ICOS) were positively correlated with the infiltration level of CD4^+ memory T cell, but negatively correlated with the infiltration level of activated mast cell. ICOS gene expression was an independent prognostic factor for survival of patients with cervical cancer(P=0.019, HR 0.687, 95% CI 0.503-0.939). Conclusion This study indicates that tumor-infiltrating immune cells play an important role in the prognosis of patients with cervical cancer, and reveal potential biomarkers and targets for immunotherapy of cervical cancer.