Department of Pathology, Division of Anatomic Pathology.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Virginia, Charlottesville, VA.
Am J Surg Pathol. 2020 Sep;44(9):1184-1191. doi: 10.1097/PAS.0000000000001506.
Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.
肿瘤细胞表达主要组织相容性复合体 (MHC) Ⅰ类是抗原呈递和适应性免疫识别所必需的。MHC Ⅰ类表达缺失或减少被认为导致了某些上皮肿瘤的免疫治疗抵抗，但以前尚未在宫颈和外阴癌中进行过研究。鉴于抗程序性细胞死亡 1 (PD-1) 检查点抑制剂被用于治疗程序性细胞死亡配体 1 (PD-L1) 阳性的复发性和转移性宫颈鳞状细胞癌，鉴定出 MHC Ⅰ类缺失的肿瘤对于优化免疫治疗候选药物的选择具有临床意义。对 58 例人乳头瘤病毒相关的宫颈和外阴病变进行了 PD-L1 和 MHC Ⅰ类 A、B、C 重链（MHC Ⅰ类）的免疫组化联合检测，包括 27 例鳞状上皮内病变（SIL）和 31 例浸润性鳞状细胞癌（SCC）。尽管 84%的 SCC 和 22%的 SIL 为 PD-L1 阳性，但 35.5%（11/31）的 SCC 和 18.5%（5/27）的 SIL 也显示出 MHC Ⅰ类的克隆性或完全缺失。在 PD-L1 阳性（10/26，38%）与 PD-L1 阴性 SCC（1/5，20%）相比，MHC Ⅰ类表达缺失更为常见。总之，超过三分之一的人乳头瘤病毒相关的宫颈和外阴 SCC 显示出 MHC Ⅰ类表达的克隆性或完全缺失，包括许多 PD-L1 阳性病例。这表明，针对 PD-1/PD-L1 轴的检查点抑制剂的疗效可能在一部分宫颈和外阴鳞状肿瘤中受到限制，因为 MHC Ⅰ类表达缺失导致与适应性免疫系统的相互作用受损。
