Department of Pathology, University of Virginia, Charlottesville, VA, USA.
Department of Pathology, Georgetown University, Washington, DC, USA.
Mod Pathol. 2021 Mar;34(3):627-636. doi: 10.1038/s41379-020-00682-w. Epub 2020 Oct 3.
Major histocompatibility complex (MHC) class I is a membrane-bound protein complex expressed on nucleated human cells. MHC class I presents intracellular protein fragments to cytotoxic T cells and triggers an activation cascade upon neoantigen detection by these cells. MHC class I loss by tumor cells decreases tumor neoantigen presentation to the immune system and therefore represents a possible mechanism of immunotherapeutic resistance even among cancers that otherwise appear to be good candidates for checkpoint inhibition, such as mismatch repair (MMR)-deficient and PD-L1-positive malignancies. We herein assess MHC class I expression in a range of endometrial carcinomas, including MMR-deficient and PD-L1-positive cancers. Immunohistochemical staining for combined MHC class I A-, B-, and C-heavy chains was performed on 76 cases of endometrial carcinoma and was classified as present, subclonally lost, or diffusely lost. Tumoral PD-L1 expression, PD-L1 combined positive score, and CD3-positive T lymphocytes were also quantified. Forty-two percent of tumors showed loss of MHC class I expression, either in a subclonal (26%) or diffuse (16%) pattern. This included 46% of MMR-deficient and 25% of PD-L1-positive cancers. These findings suggest that tumoral MHC class I status may be an important factor to consider when selecting endometrial cancer patients for checkpoint inhibition.
主要组织相容性复合体 (MHC) Ⅰ类是一种表达在有核人类细胞上的膜结合蛋白复合物。MHC Ⅰ类将细胞内的蛋白质片段呈递给细胞毒性 T 细胞，并在这些细胞检测到新抗原时触发激活级联反应。肿瘤细胞中 MHC Ⅰ类的丢失会减少肿瘤新抗原向免疫系统的呈递，因此即使在其他看起来是检查点抑制良好候选者的癌症中，如错配修复 (MMR) 缺陷和 PD-L1 阳性恶性肿瘤，也代表了一种免疫治疗抵抗的可能机制。我们在此评估了一系列子宫内膜癌中 MHC Ⅰ类的表达，包括 MMR 缺陷和 PD-L1 阳性癌症。对 76 例子宫内膜癌进行了 MHC Ⅰ类 A、B 和 C 重链的联合免疫组织化学染色，并将其分类为存在、亚克隆丢失或弥漫性丢失。还定量了肿瘤 PD-L1 表达、PD-L1 联合阳性评分和 CD3 阳性 T 淋巴细胞。42%的肿瘤显示 MHC Ⅰ类表达丢失，无论是亚克隆（26%）还是弥漫性（16%）模式。这包括 46%的 MMR 缺陷和 25%的 PD-L1 阳性癌症。这些发现表明，肿瘤 MHC Ⅰ类状态可能是选择子宫内膜癌患者进行检查点抑制时需要考虑的一个重要因素。
