Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.

新辅助免疫检查点阻断已显示出有希望的临床活性。在这里，我们在一项临床试验 (NCT02919683) 中描述了接受新辅助抗 PD-1 或​​抗 PD-1/CTLA-4 治疗的口腔癌患者肿瘤浸润和循环免疫细胞的早期动力学。在免疫治疗期间克隆扩增的肿瘤浸润性 CD8 T 细胞表达增强的组织驻留记忆和细胞毒性程序，这些程序在治疗前就已经活跃，支持快速反应的能力。系统性靶点发现表明，治疗后有反应的患者中扩增的肿瘤 T 细胞克隆识别了多种自身抗原，包括癌症特异性抗原 MAGEA1。治疗还诱导了全身免疫反应，其特征是激活的 T 细胞扩增，富含肿瘤浸润 T 细胞克隆型，包括治疗前无法检测到的预先存在的和新出现的克隆型。活化的血液 CD8 T 细胞（尤其是治疗前 PD-1 阳性 KLRG1 阴性 T 细胞）的频率与肿瘤内病理反应密切相关。这些结果证明了新辅助检查点阻断如何诱导局部和全身肿瘤免疫。