Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
Cancer Immunol Res. 2014 Nov;2(11):1071-9. doi: 10.1158/2326-6066.CIR-14-0005. Epub 2014 Aug 12.
Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer. Robust cellular immune responses are associated with excellent outcomes in patients with MCC, but these responses are typically absent. We determined the prevalence and reversibility of major histocompatibility complex class I (MHC-I) downregulation in MCC, a potentially reversible immune-evasion mechanism. Cell-surface MHC-I expression was assessed on five MCC cell lines using flow cytometry as well as immunohistochemistry on tissue microarrays representing 114 patients. Three additional patients were included who had received intralesional IFN treatment and had evaluable specimens before and after treatment. mRNA expression analysis of antigen presentation pathway genes from 35 MCC tumors was used to examine the mechanisms of downregulation. Of note, 84% of MCCs (total n = 114) showed reduced MHC-I expression as compared with surrounding tissues, and 51% had poor or undetectable MHC-I expression. Expression of MHC-I was lower in polyomavirus-positive MCCs than in polyomavirus-negative MCCs (P < 0.01). The MHC-I downregulation mechanism was multifactorial and did not depend solely on HLA gene expression. Treatment of MCC cell lines with ionizing radiation, etoposide, or IFN resulted in MHC-I upregulation, with IFNs strongly upregulating MHC-I expression in vitro, and in 3 of 3 patients treated with intralesional IFNs. MCC tumors may be amenable to immunotherapy, but downregulation of MHC-I is frequently present in these tumors, particularly those that are positive for polyomavirus. This downregulation is reversible with any of several clinically available treatments that may thus promote the effectiveness of immune-stimulating therapies for MCC.
默克尔细胞癌 (Merkel cell carcinoma, MCC) 是一种侵袭性的、与多瘤病毒相关的皮肤癌。在 MCC 患者中，强大的细胞免疫反应与良好的预后相关，但这些反应通常不存在。我们确定了 MCC 中主要组织相容性复合体 I (major histocompatibility complex class I, MHC-I) 下调的普遍性和可逆转性，这是一种潜在的免疫逃逸机制。我们使用流式细胞术评估了五种 MCC 细胞系的细胞表面 MHC-I 表达，并使用组织微阵列进行了免疫组织化学检测，这些微阵列代表了 114 名患者。另外还纳入了 3 名接受局部 IFN 治疗且在治疗前后有可评估标本的患者。我们使用 35 个 MCC 肿瘤的抗原呈递途径基因的 mRNA 表达分析来研究下调的机制。值得注意的是，与周围组织相比，84%的 MCC（总 n = 114）显示 MHC-I 表达降低，51%的 MCC 表达较差或无法检测到 MHC-I。与多瘤病毒阴性的 MCC 相比，多瘤病毒阳性的 MCC 中 MHC-I 的表达较低（P < 0.01）。MHC-I 下调的机制是多因素的，并不完全依赖于 HLA 基因表达。用电离辐射、依托泊苷或 IFN 处理 MCC 细胞系会导致 MHC-I 上调，IFN 在体外强烈上调 MHC-I 表达，在接受局部 IFN 治疗的 3 名患者中也是如此。MCC 肿瘤可能适合免疫治疗，但这些肿瘤中 MHC-I 的下调经常存在，特别是那些多瘤病毒阳性的肿瘤。这种下调是可以逆转的，几种临床可用的治疗方法都可能促进免疫刺激疗法治疗 MCC 的有效性。
