Yang-Chun Feng, Zhen-Zhen Cheng, Yan-Chun Huang, Xiu-Min Ma
Clinical Laboratory Center, The First Affiliated Hospital of Xinjiang Medical University Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, People's Republic of China.
Medicine (Baltimore). 2017 Jun;96(25):e7270. doi: 10.1097/MD.0000000000007270.
The difference of PD-L1 expression between only HPV-positive patients and premalignant cervical lesion patients did not be reported in present studies. And to test the PD-L1 expression in some cervical cell lesion studies using cervical exfoliated cells sample also was ignored. Meanwhile, the PD-L1 expression as a predictive biomarker still existed controversy. So in the study, first to compare the expression of PD-L1 between only HPV-positive patients and premalignant cervical lesion patients, then to research the association between PD-L1 and HPV status, lastly to explore the possible prognostic value for HPV treatment in premalignant cervical lesion patients.Cervical exfoliated cells samples of 54 premalignant cervical lesion patients with HPV16 infection were collected; meanwhile the cervical exfoliated cells samples from 20 healthy women without HPV infection and 20 patients with only HPV16 infection but cervical cytology normal were collected as 2 control groups. Flow-through hybridization and gene chip (FHGC) was used to detect the HPV type, the PD-L1 expression was tested by Flow cytometry analysis, the methylation-sensitive high-resolution melting (MS-HRM) was used to test the HPV16 L1 gene methylation. The 54 premalignant cervical lesion patients were followed up in 18 months to assess the prognostic value of PD-L1 for HPV treatment.The PD-L1 positive cell rate and mean fluorescence intensity of PD-L1 positive cell in premalignant cervical lesion patients with HPV16 infection were higher than 2 control groups. Mean fluorescence intensity of PD-L1 positive cell were increased in 54 cases when existing multiple HPV status and high HPV16-L1 gene methylation (L1 gene methylation more than 50%). High PD-L1 expression (PD-L1 positive cell rate more than 10%), high HPV16-L1 gene methylation, and multiple HPV infection status could prolong the time to clean HPV infection by Kaplan-Meier analysis. Multivariate Cox proportional hazards analysis also showed that all of high PD-L1 expression, high HPV-L1 methylation, and multiple HPV infection status should increase the risk of HPV unclearance in premalignant cervical lesion patients; the hazard ratio (HR) was 2.043 (CI: 1.050-3.973), 2.797 (CI: 1.277-6.122), and 3.050 (CI: 1.406-6.615).PD-L1 expression only was correction with HPV infection when the infection induced the cervical cells to create the lesion. PD-L1 was the risk factor of HPV unclearance in premalignant cervical lesion patients, so anti-PD-L1 therapy could be a potential effectiveness way of HPV infection in premalignant cervical lesion patients.
目前的研究未报道仅HPV阳性患者与宫颈上皮内瘤变患者之间PD-L1表达的差异。并且在一些使用宫颈脱落细胞样本的宫颈细胞病变研究中，对PD-L1表达的检测也被忽视了。同时，PD-L1表达作为一种预测生物标志物仍存在争议。因此，在本研究中，首先比较仅HPV阳性患者与宫颈上皮内瘤变患者之间PD-L1的表达，然后研究PD-L1与HPV状态之间的关联，最后探讨PD-L1对宫颈上皮内瘤变患者HPV治疗的可能预后价值。收集了54例HPV16感染的宫颈上皮内瘤变患者的宫颈脱落细胞样本；同时收集了20例无HPV感染的健康女性和20例仅HPV16感染但宫颈细胞学正常患者的宫颈脱落细胞样本作为2个对照组。采用导流杂交基因芯片（FHGC）检测HPV类型，通过流式细胞术分析检测PD-L1表达，采用甲基化敏感高分辨率熔解曲线分析（MS-HRM）检测HPV16 L1基因甲基化。对54例宫颈上皮内瘤变患者进行18个月的随访，以评估PD-L1对HPV治疗的预后价值。HPV16感染的宫颈上皮内瘤变患者中PD-L1阳性细胞率及PD-L1阳性细胞平均荧光强度均高于2个对照组。54例患者中，当存在多种HPV状态及高HPV16-L1基因甲基化（L1基因甲基化>50%）时，PD-L1阳性细胞平均荧光强度升高。通过Kaplan-Meier分析，高PD-L1表达（PD-L1阳性细胞率>10%）、高HPV16-L1基因甲基化及多种HPV感染状态可延长HPV感染清除时间。多因素Cox比例风险分析也显示，高PD-L1表达、高HPV-L1甲基化及多种HPV感染状态均增加宫颈上皮内瘤变患者HPV清除的风险；风险比（HR）分别为2.043（95%CI：1.050-3.973）、2.797（95%CI：1.277-6.122）和3.050（95%CI：1.406-6.615）。仅当HPV感染诱导宫颈细胞发生病变时，PD-L1表达才与HPV感染相关。PD-L1是宫颈上皮内瘤变患者HPV清除的危险因素，因此抗PD-L1治疗可能是宫颈上皮内瘤变患者HPV感染的一种潜在有效治疗方法。
