Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma.
Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma.
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DOI：
10.1158/0008-5472.can-12-2384
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发表时间：
2013-03-15
期刊：
影响因子：
11.2
通讯作者：
Pai SI
中科院分区：
文献类型：
--
作者：
Lyford-Pike S;Peng S;Young GD;Taube JM;Westra WH;Akpeng B;Bruno TC;Richmon JD;Wang H;Bishop JA;Chen L;Drake CG;Topalian SL;Pardoll DM;Pai SI
人乳头瘤病毒相关的头颈部鳞状细胞癌（HPV-HNSCC）起源于扁桃体，扁桃体是协调对口腔感染的免疫的主要淋巴器官。尽管它的位置，病毒逃脱免疫消除过程中恶性转化和进展。在这里，我们为PD-1：PD-L1通路在HPV-HNSCC免疫抵抗中的作用提供了证据。我们证明了PD-L1在扁桃体隐窝中的膜表达，扁桃体隐窝是HPV初始感染的部位。在淋巴细胞高度浸润的HPV-HNSCC中，肿瘤细胞和CD 68+肿瘤相关巨噬细胞（TAM）上的PD-L1表达在地理上定位于淋巴细胞前沿的部位，而大多数CD 8+肿瘤浸润淋巴细胞（TIL）表达高水平的PD-1（抑制性PD-L1受体）。在HPV+ PD-L1（+）肿瘤中发现了显著水平的干扰素-γ（IFN-γ）mRNA，IFN-γ是PD-L1表达的主要细胞因子诱导剂。我们的研究结果支持PD-1：PD-L1相互作用在创建初始病毒感染的“免疫特权”位点和随后的适应性免疫抵抗（一旦肿瘤建立）中的作用，并提出了在HPV-HNSCC患者中治疗阻断该途径的基本原理。
Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We demonstrate membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor associated macrophages (TAMs) is geographically localized to sites of lymphocyte fronts, while the majority of CD8+ tumor infiltrating lymphocytes (TILs) express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for interferon-γ (IFN-γ), a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an “immune-privileged” site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.