宫颈鳞癌患者外周血HPV16 E6和E7特异性免疫反应及预后分析

doi:10.3760/cma.j.cn113030-20201022-00577

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摘要目的研究宫颈鳞癌患者外周血HPV16 E6和E7特异性免疫反应与临床特征和预后关系。方法收集2013—2015年间新疆医科大学附属肿瘤医院经病理明确诊断的 72例宫颈鳞癌初治患者,并同期入组 75例体检者作为健康对照。采用酶联免疫斑点法检测患者治疗前外周血中经抗原重叠肽E6和E7刺激的T细胞特异性免疫反应。χ²检验和非参数检验分析宫颈鳞癌组和健康对照组的特异性免疫反应的频率和强度表达差异;Spearman法检验抗原特异性免疫反应和T细胞亚群相关性;log-rank法和Cox模型用于单因素和多因素预后分析。结果宫颈鳞癌组HPV16 E6和E7特异性T细胞免疫反应频率均高于健康对照组(51.39%∶29.33%, P=0.006和45.83%∶25.33%, P=0.009),同时免疫反应强度也均高于健康对照组(20.00 SFC/10⁶∶10.76 SFC/10⁶, P<0.001和16.17 SFC/10⁶∶10.72 SFC/10⁶, P=0.017)。宫颈鳞癌组HPV16 E6特异性T细胞免疫反应强度和外周血CD⁺₄/CD⁺₈呈正相关(r=0.279,P=0.018);HPV16 E7抗原特异性T细胞免疫和外周血NK细胞占比和反应强度呈正相关(r=0.274,P=0.020)。单因素和多因素分析均显示治疗模式(放疗与放化疗 HR=2.918,95%CI为 1.454~5.854,P=0.003)和E6特异性免疫应答(应答与无应答 HR=0.491,95%CI为 0.243~0.990,P=0.047)是影响患者预后因素。E6特异性免疫应答组患者 5年总生存率明显高于无应答组(64%∶41%,P=0.041)。结论 HPV16 E6特异性T细胞免疫反应强度与CD⁺₄/CD⁺₈呈正相关,无应答与单纯放疗导致宫颈鳞癌患者预后不良。

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	蔡鸿超
	袁源亮
	玛依努尔·阿里甫
	王若峥

关键词 ： T细胞免疫, 人乳头瘤病毒, 宫颈肿瘤/同步放化疗法, 预后

Abstract：Objective To investigate the relationship between human papilloma virus (HPV)16 E6/7-specific T cell immune response in the periphral blood and clinical features and prognosis of patients with cervical squamous cell carcinoma (CSCC). Methods Seventy-two patients pathologically diagnosed with CSCC admitted to Affiliated Tumor Hospital of Xinjiang Medical University from June 2013 to October 2015, and 75 healthy controls were enrolled in this study. The special responses of peripheral blood T cells to E6 and E7 overlapping peptides before treatment were detected by enzyme-linked immunosorbent assay (ELISA). The differences of frequency and intensity expression of specific immune responses between two groups were analyzed by chi-square χ² test and nonparametric test. The correlation between antigen-specific immune response and T cell subsets was analyzed by Spearman test. Log-rank test and Cox's regression model were employed for univariate and multivariate prognostic analyses. Results The frequencies of HPV16 E6-ad E7-specific T cell responses in CSCC patients were significantly higher than those in healthy controls (51.39% vs. 29.33%,P=0.006 and 45.83% vs.25.33%,P=0.009), and the mean intensities were also considerably higher than those in healthy controls (20.00 SFC/10⁶ vs.10.76 SFC/10⁶,P<0.001 and 16.17 SFC/10⁶ vs.10.72 SFC/10⁶,P=0.017). The intensity of HPV16 E6-specific T cell immune response was positively correlated with the CD⁺₄/CD⁺₈ ratio in the peripheral blood of CSCC patients (r=0.279,P=0.018). And a strong correlation was noted between E7-specific T cell immune response intensity and increasing proportion of NK+ cells (r=0.274,P=0.020). Univariate and multivariate analyses showed that therapeutic mode (radiotherapy vs. concurrent chemoradiotherapy, HR=2.918, 95%CI 1.454-5.854, P=0.003) and E6-specific T cell response (response group vs. no response group, HR=0.491, 95%CI 0.243-0.99,P=0.047) were the independent prognostic factors influencing the clinical prognosis. The 5-year overall survival in patients with HPV16 E6-specific T cell responses was significantly higher than that in the no response group (64% vs.41%,P=0.041). Conclusions The intensity of HPV16 E6-specific T cell immune response is positively correlated with the CD⁺₄/CD⁺₈ ratio. No HPV16 E6-specific T cell response and radiotherapy alone are more likely to cause poor prognosis of CSCC patients.

Key words： T cell immune Human papilloma virus Uterine cervical neoplasm/concurrent chemoradiotherapy Prognosis

收稿日期: 2020-10-22

基金资助:国家自然科学基金(U1603282);中国医学科学院肿瘤免疫研究和放疗研究重点实验室专项课题(2019PT310021)

通讯作者: 王若峥,Email:wrz8526@vip.163.com

引用本文:

蔡鸿超,袁源亮,玛依努尔·阿里甫等. 宫颈鳞癌患者外周血HPV16 E6和E7特异性免疫反应及预后分析[J]. 中华放射肿瘤学杂志, 2021, 30(4): 357-362.

Cai Hongchao,Yuan Yuanliang,Mayinuer Alifu et al. Association between human papilloma virus 16 E6 and E7-specific T cell immune response and clinical prognosis of patients with cervical squamous cell carcinoma[J]. Chinese Journal of Radiation Oncology, 2021, 30(4): 357-362.

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