Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Guangzhou Laboratory, Guangzhou, Guangdong 510005, China.
Cell. 2022 Aug 4;185(16):2918-2935.e29. doi: 10.1016/j.cell.2022.06.018. Epub 2022 Jul 7.
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前景的临床活性。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 治疗的口腔癌患者的肿瘤浸润和循环免疫细胞的早期动力学。在免疫治疗过程中克隆扩增的肿瘤浸润 CD8 T 细胞表达上调的组织驻留记忆和细胞毒性程序，这些程序在治疗前已经活跃，支持快速反应的能力。系统的靶标发现表明，在有反应的患者中，治疗扩展的肿瘤 T 细胞克隆识别了几种自身抗原，包括癌症特异性抗原 MAGEA1。治疗还诱导了一种以激活的 T 细胞扩增为特征的系统性免疫反应，这些 T 细胞富含肿瘤浸润性 T 细胞克隆型，包括治疗前无法检测到的既有和新出现的克隆型。激活的血液 CD8 T 细胞的频率，特别是治疗前 PD-1 阳性 KLRG1 阴性 T 细胞的频率，与肿瘤内病理反应强烈相关。这些结果表明了新辅助检查点阻断如何诱导局部和全身肿瘤免疫。
