Department of Radiation Oncology, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Int J Radiat Oncol Biol Phys. 2018 Sep 1;102(1):137-145. doi: 10.1016/j.ijrobp.2018.05.002. Epub 2018 Jun 29.
Programmed death-1 (PD-1) inhibitors are approved for the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Ongoing and planned randomized phase 3 trials are testing the benefit of combining PD-1/programmed death-ligand 1 (PD-L1) inhibitors with chemoradiation for patients with locoregionally confined SCCHN. Few studies have investigated relationships among potential predictive pathologic biomarkers such as PD-L1, PD-L2, and PD-1 in this population and associations between these markers and clinical characteristics.
We retrospectively reviewed records and pathology from 81 patients with locoregional oropharynx SCCHN treated with curative intent. Samples were analyzed for PD-L1, PD-L2, PD-1, CD8, and CD56 expression using immunohistochemistry. Human papilloma virus (HPV) status was determined by p16-immunohistochemistry and confirmed by in situ hybridization or polymerase chain reaction-based HPV typing. Correlations between HPV status, clinical features, and recurrence status with immune markers in both tumor and tumor-associated stroma were determined. Hazard ratios were estimated via Cox proportional hazards model.
Tumor PD-L1 expression was inversely associated with age (P = .01) and the highest levels of expression (>30% of tumor cells) were observed in HPV-associated tumors. There was a correlation between tumor and stromal PD-L1 expression (P = < .0001). PD-1 and CD8 expression within tumor deposits was associated with HPV status (P = 0.003 and P = .008, respectively) and decreased local recurrence (P = .001 and P < .001, respectively). In addition to the association between tumor and stromal PD-1 (P < .0001), PD-1 was also correlated with tumor PD-L1 expression (P < .001). CD56+ natural killer cell infiltrates correlated with PD-L1 expression.
In patients with untreated oropharyngeal SCCHN, HPV-associated tumors displayed the highest levels of PD-L1 expression and PD-1+ and CD8+ immune cells. Locally recurrent tumors had lower levels of PD-L1, PD-1, and CD-8 positivity. Whereas almost all SCCHN tumors had CD56+ infiltrating natural killer cells, most tumors didn't have PD-L2 expression. These associations may help predict which patients may benefit most from immunotherapeutic approaches.
程序性死亡受体-1（PD-1）抑制剂已被批准用于治疗复发性和转移性头颈部鳞状细胞癌（SCCHN）患者。正在进行和计划的随机 3 期试验正在测试将 PD-1/程序性死亡配体 1（PD-L1）抑制剂与放化疗联合用于局部局限 SCCHN 患者的益处。很少有研究调查了该人群中 PD-L1、PD-L2 和 PD-1 等潜在预测性病理生物标志物之间的关系，以及这些标志物与临床特征之间的关系。
我们回顾性分析了 81 例接受根治性治疗的局部或咽 SCCHN 患者的病历和病理记录。使用免疫组织化学法分析 PD-L1、PD-L2、PD-1、CD8 和 CD56 的表达。通过 p16-免疫组化法确定人乳头瘤病毒（HPV）状态，并通过原位杂交或聚合酶链反应 HPV 分型法进行确认。确定 HPV 状态、临床特征和肿瘤与肿瘤相关基质中免疫标志物之间的相关性与复发状态。通过 Cox 比例风险模型估计风险比。
肿瘤 PD-L1 表达与年龄呈负相关（P =.01），且 HPV 相关肿瘤中观察到最高水平的表达（>30%的肿瘤细胞）。肿瘤和肿瘤相关基质中 PD-L1 表达之间存在相关性（P = <.0001）。肿瘤沉积物中 PD-1 和 CD8 的表达与 HPV 状态相关（P = 0.003 和 P =.008，分别），并降低了局部复发（P =.001 和 P <.001，分别）。除了肿瘤和基质 PD-1 之间的关联（P <.0001）外，PD-1 还与肿瘤 PD-L1 表达相关（P <.001）。CD56+自然杀伤细胞浸润与 PD-L1 表达相关。
在未经治疗的咽 SCCHN 患者中，HPV 相关肿瘤显示出最高水平的 PD-L1 表达和 PD-1+和 CD8+免疫细胞。局部复发肿瘤的 PD-L1、PD-1 和 CD-8 阳性率较低。尽管几乎所有的 SCCHN 肿瘤都有 CD56+浸润性自然杀伤细胞，但大多数肿瘤没有 PD-L2 表达。这些关联可能有助于预测哪些患者最有可能从免疫治疗方法中受益。
