Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis, St. Louis, Missouri.
Clin Cancer Res. 2020 Feb 1;26(3):679-689. doi: 10.1158/1078-0432.CCR-19-2209. Epub 2019 Oct 23.
Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse.
Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and challenge assays.
We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen.
Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.
对于人乳头瘤病毒阴性头颈部鳞状细胞癌患者，手术切除原发肿瘤并进行区域淋巴结清扫仍然是首选治疗方法。然而，即使能够获得病理无病切缘，局部区域和/或远处疾病复发率仍然很高。围手术期免疫治疗可能改善预后，但支持临床应用新辅助或辅助治疗的机制数据很少。
使用程序性死亡受体 1（PD-1）单克隆抗体治疗两种具有明确 T 细胞抗原的口腔癌同源模型，在切除原发肿瘤之前或之后进行，并用功能和挑战试验探索抗原特异性 T 细胞反应。
我们证明了针对多个独立肿瘤抗原的 T 细胞具有功能性免疫优势。针对亚优势抗原的 T 细胞表达更高水平的 PD-1。新辅助而不是辅助 PD-1 免疫检查点阻断打破了免疫优势，并诱导针对优势和亚优势抗原的 T 细胞反应。使用缺乏免疫优势抗原的肿瘤作为抗原逃逸模型，新辅助 PD-1 免疫检查点阻断诱导针对缺乏免疫优势但保留亚优势抗原的肿瘤细胞的效应 T 细胞免疫。当与完全手术切除相结合时，新辅助 PD-1 免疫检查点阻断导致形成能够预防缺乏免疫优势但保留亚优势抗原的肿瘤植入的免疫记忆。
这些结果共同表明，T 细胞中 PD-1 的表达参与了进展性肿瘤中独立 T 细胞克隆之间功能性免疫优势的机制，并支持在可手术切除的癌患者中使用新辅助 PD-1 免疫检查点阻断。
