Abstract：
Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.
摘要：
癌症患者通常接受靶向程序性死亡配体1（PD-L1）和细胞毒性T淋巴细胞抗原4（CTLA4）的抗体组合。我们在头颈部鳞状细胞癌（HNSCC）中进行了机会窗研究，以检查抗CTLA4对抗PD-L1治疗的贡献。与治疗前活检的单细胞谱分析将T细胞扩增鉴定为早期反应标志物。在肿瘤中，抗PD-L1触发了大部分CD8+T细胞的扩增，而联合治疗扩增CD4+和CD8+T细胞。这样的CD4+T细胞表现出活化的T辅助1(Th1)表型。CD4+和CD8+T细胞与表达T细胞归巢因子的树突状细胞或产生抗体的浆细胞共定位并被其包围。T细胞受体追踪表明，抗CTLA4，而不是抗PD-L1，触发CD4+幼稚/中枢记忆T细胞从肿瘤引流淋巴结（tdLN）的运输，通过血，T细胞获得Th1表型的肿瘤。因此，CD4+T细胞活化和来自tdLN的募集是HNSCC中对抗PD-L1加抗CTLA4的早期反应的标志。
