PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.
PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.
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DOI：
10.1158/2326-6066.cir-13-0034
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发表时间：
2013-07
影响因子：
10.1
通讯作者：
Taube JM
中科院分区：
文献类型：
--
作者：
Lipson EJ;Vincent JG;Loyo M;Kagohara LT;Luber BS;Wang H;Xu H;Nayar SK;Wang TS;Sidransky D;Anders RA;Topalian SL;Taube JM
默克尔细胞癌（MCC）是一种致命的病毒相关癌症，缺乏有效的治疗晚期疾病。阻断PD-1/PD-L1通路的药物已在晚期实体恶性肿瘤患者中显示出客观、持久的肿瘤消退，且疗效与肿瘤微环境中的PD-L1表达相关。为了研究MCC是否可能是PD-1/PD-L1阻断的靶点，我们检测了MCC PD-L1表达及其与肿瘤浸润淋巴细胞（TIL）、默克尔细胞多瘤病毒（MCPyV）和总生存期的相关性。采用免疫组织化学方法对49例患者的67份MCC标本进行肿瘤细胞和TIL的PD-L1表达评估，并对免疫浸润进行表型表征。分别在49%和55%的患者中观察到肿瘤细胞和TIL PD-L1表达。在含有PD-L1（+）肿瘤细胞的标本中，97%（28/29）显示与免疫浸润存在地理相关性。在具有中度-重度TIL强度的标本中，100%（29/29）的肿瘤细胞显示PD-L1表达。在MCPyV DNA的存在、活跃的炎症反应和肿瘤细胞PD-L1表达之间也观察到了显著的相关性：MCPyV（-）肿瘤细胞都是PD-L1（-）。总之，这些发现表明，局部肿瘤特异性和潜在的MCPyV特异性免疫应答驱动肿瘤PD-L1表达，与先前在黑色素瘤和头颈部鳞状细胞癌中的观察结果相似。在多变量分析中，PD-L1（−）MCC与总生存率较差独立相关（风险比3.12; 95% CI，1.28-7.61; p=0.012）。这些发现表明，当存在MCPyV时，内源性免疫应答促进MCC微环境中的PD-L1表达，并为研究MCC患者阻断PD-1/PD-L1的治疗提供了依据。
Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have demonstrated objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TILs), Merkel cell polyomavirus (MCPyV), and overall survival. Sixty-seven MCC specimens from 49 patients were assessed with immunohistochemistry for PD-L1 expression by tumor cells and TILs, and immune infiltrates were characterized phenotypically. Tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In specimens with PD-L1(+) tumor cells, 97% (28/29) demonstrated a geographic association with immune infiltrates. Among specimens with moderate-severe TIL intensities, 100% (29/29) demonstrated PD-L1 expression by tumor cells. Significant associations were also observed between the presence of MCPyV DNA, a brisk inflammatory response, and tumor cell PD-L1 expression: MCPyV(−) tumor cells were uniformly PD-L1(−). Taken together, these findings suggest that a local tumor-specific and potentially MCPyV-specific immune response drives tumor PD-L1 expression, similar to previous observations in melanoma and head and neck squamous cell carcinomas. In multivariate analyses, PD-L1(−) MCCs were independently associated with worse overall survival (hazard ratio 3.12; 95% CI, 1.28-7.61; p=0.012). These findings suggest that an endogenous immune response promotes PD-L1 expression in the MCC microenvironment when MCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC.