HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma
HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma
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HPV 阳性状态与头颈鳞状细胞癌免疫微环境发炎以及抗 PD-1 治疗反应改善相关
DOI：
10.1038/s41598-019-49771-0
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发表时间：
2019-09-16
影响因子：
4.6
通讯作者：
Dong, Zhong-Yi
中科院分区：
文献类型：
--
作者：
Wang, Jian;Sun, Hao;Dong, Zhong-Yi
化疗和放疗主要改善人乳头瘤病毒（HPV）相关头颈部鳞状细胞癌（HNSCC）患者的临床结局。这种优越性在使用免疫检查点抑制剂治疗时是否继续尚不清楚。本研究旨在确定HPV状态对程序性细胞死亡1（PD-1）/配体1（PD-L1）抑制剂治疗的预测价值和潜在机制。我们对HPV状态与PD-L1、肿瘤突变负荷（TMB）和炎症相关免疫细胞和分子之间的关系进行了综合分析，基于对储存库数据库和切除的HNSCC标本的分析。对总生存期（OS）和客观缓解率（ORR）的汇总分析表明，HPV阳性患者从PD-1/PD-L1抑制剂中获益大于HPV阴性患者（OS：风险比（HR）= 0.71，p = 0.02; ORR：21.9% vs 14.1%，比值比（OR）= 1.79，p = 0.01）。对公共数据库和切除的HNSCC标本的分析显示，HNSCC中HPV状态与PD-L1表达和TMB无关。然而，HPV感染显著增加T细胞浸润，免疫效应细胞活化和T细胞受体的多样性。值得注意的是，HPV阳性与免疫细胞溶解活性增加和T细胞炎症基因表达谱相关。这项工作提供的证据表明，HPV状态可用于预测PD-1抑制剂在HNSCC中的有效性，独立于PD-L1表达和TMB，并且可能由HPV感染诱导的炎症免疫微环境引起。
Chemotherapy and radiotherapy predominantly improve the clinical outcomes of patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC). Whether this superiority goes on when treated with immune checkpoint inhibitors is still unclear. This study sought to determine the predictive value and potential mechanisms of HPV status for the treatment of programmed cell death 1 (PD-1)/ligand 1(PD-L1) inhibitors. We conducted an integrated analysis of the relationships between HPV status and PD-L1, tumor mutation burden (TMB) and inflammation-related immune cells and molecules, based on the analysis of repository databases and resected HNSCC specimens. The pooled analysis of overall survival (OS) and objective response rate (ORR) suggested that HPV-positive patients benefited more from PD-1/PD-L1 inhibitors than HPV-negative patients (OS: hazard ratio (HR) = 0.71,p= 0.02; ORR: 21.9% vs 14.1%, odds ratio (OR) = 1.79,p= 0.01). Analysis of public databases and resected HNSCC specimens revealed that HPV status was independent of PD-L1 expression and TMB in HNSCC. However, HPV infection significantly increased T-cell infiltration, immune effector cell activation and the diversity of T-cell receptors. Notably, HPV-positivity correlated with increased immune cytolytic activity and a T-cell-inflamed gene expression profile. This work provides evidence that HPV status can be used to predict the effectiveness of PD-1 inhibitors in HNSCC, independently of PD-L1 expression and TMB, and probably results from an inflamed immune microenvironment induced by HPV infection.