Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Mod Pathol. 2020 Apr;33(4):603-615. doi: 10.1038/s41379-019-0392-8. Epub 2019 Oct 25.
Extranodal NK/T-cell lymphoma is an aggressive lymphoma that is strongly associated with Epstein-Barr virus infection. Although some extranodal NK/T-cell lymphoma patients have shown responses to immune checkpoint blockade, biomarkers for predicting extranodal NK/T-cell lymphoma patient response to immunotherapy have not yet been defined. To understand the tumor immune microenvironment, we analyzed the expression of 579 immune-related genes and characterized the immune cells using immunohistochemistries and in situ hybridization for EBER. Based on comprehensive analyses, we developed an immune subtyping model that classifies extranodal NK/T-cell lymphoma patients into four tumor immune microenvironment subgroups using three immunohistochemical markers (FoxP3, PD-L1, and CD68). The four tumor immune microenvironment subgroups were named immune tolerance, immune evasion-A, immune evasion-B, and immune silenced. The immune tolerance group was characterized by high-Treg counts and was frequently observed in early stage, and nasal extranodal NK/T-cell lymphoma. The immune evasion group showed high cytotoxic T-cell counts and high PD-L1 expression but low Treg counts. In the immune-silenced group, almost all immune responses were exhausted, most patients were at an advanced stage, and had the poorest disease prognosis among the tumor immune microenvironment subgroups. In some patients (n = 3), a shift in the tumor immune microenvironment subgroup classification was observed in sequential biopsies. The response rate to pembrolizumab, an anti-PD-1 antibody, was 100% (1/1) in the immune tolerance group, 60% (3/5) in the immune evasion group, and 0% (0/5) in the immune-silenced group. We classified extranodal NK/T-cell lymphoma into four tumor immune microenvironment subgroups using a new classification system. In conclusion, we propose that the tumor immune microenvironment of extranodal NK/T-cell lymphoma may change during disease progression and may serve as a useful biomarker for immunotherapy.
结外 NK/T 细胞淋巴瘤是一种侵袭性淋巴瘤，与 EBV 感染密切相关。虽然一些结外 NK/T 细胞淋巴瘤患者对免疫检查点阻断有反应，但尚未确定预测结外 NK/T 细胞淋巴瘤患者对免疫治疗反应的生物标志物。为了了解肿瘤免疫微环境，我们分析了 579 个免疫相关基因的表达，并通过免疫组化和 EBER 原位杂交对免疫细胞进行了特征分析。基于综合分析，我们开发了一种免疫亚分型模型，该模型使用三种免疫组化标志物（FoxP3、PD-L1 和 CD68）将结外 NK/T 细胞淋巴瘤患者分为四个肿瘤免疫微环境亚组。这四个肿瘤免疫微环境亚组分别命名为免疫耐受、免疫逃逸-A、免疫逃逸-B 和免疫沉默。免疫耐受组的特点是 Treg 计数高，多见于早期和鼻型结外 NK/T 细胞淋巴瘤。免疫逃逸组表现为高细胞毒性 T 细胞计数和高 PD-L1 表达，但 Treg 计数低。在免疫沉默组中，几乎所有的免疫反应都被耗尽，大多数患者处于晚期，在肿瘤免疫微环境亚组中预后最差。在一些患者（n=3）中，在连续活检中观察到肿瘤免疫微环境亚组分类的转变。抗 PD-1 抗体 pembrolizumab 的缓解率在免疫耐受组为 100%（1/1），在免疫逃逸组为 60%（3/5），在免疫沉默组为 0%（0/5）。我们使用新的分类系统将结外 NK/T 细胞淋巴瘤分为四个肿瘤免疫微环境亚组。总之，我们提出结外 NK/T 细胞淋巴瘤的肿瘤免疫微环境可能在疾病进展过程中发生变化，并可能作为免疫治疗的有用生物标志物。
