PDF(Pubmed)
Abstract：
An active host adaptive response is characterized by the existence of programmed cell death protein 1 (PD-1)+ /IFN-γ+ cytotoxic T cells and IFN-γ-induced PD-L1+ tumor cells (TCs), which predicts high response rate to anti-PD-1/L1 therapy. Recently, CD161 and its ligand LLT1 (CLEC2D) have been identified as an emerging checkpoint for immunotherapy. Clarifying its heterogeneous clinical expression pattern and its immune landscape is a prerequisite for maximizing the response rate of CD161 blockade therapy in a specific population of oral squamous cell carcinoma (OSCC) patients. Here, we investigated the expression pattern of CD161/LLT1 and its association with major immunocytes (T cells, B cells, NK cells, and macrophages) by multiplex immunofluorescence, immunohistochemistry, and flow cytometry in 109 OSCC tissues and 102 peripheral blood samples. TCs showed higher LLT1 levels than tumor infiltrating lymphocytes (TILs), whereas CD161 was highly expressed in CD8+ T cells at the tumor front, which was decreased in paracancerous tissue. High expression of TC-derived LLT1 (LLT1TC ) conferred poor clinical outcomes, whereas higher CD161+ and LLT1+ TILs were associated with better prognosis. Meanwhile, patients with high LLT1TC showed a decreased ratio of CD8+ /Foxp3+ T cells in situ, but CD161+ TILs correlated with more peripheral CD3+ T cells. Interestingly, treatment of OSCC patients with nivolumab (anti-PD-1) could restore tumoral CD161/LLT1 signal. Furthermore, an OSCC subgroup characterized by high LLT1+ TCs and low CD161+ CD8+ T cells showed fewer peripheral T cells and a higher risk of lymph node metastasis, leading to a shorter 5-year survival time (29%). More LLT1TC at the invasive front was another risk characteristic of exhausted T cells. In conclusion, in view of this heterogeneity, the LLT1/CD161 distribution pattern should be determined before CD161-based immunotherapy.
摘要：
主动宿主适应性反应的特征是存在程序性细胞死亡蛋白1（PD-1）/IFN-γ细胞毒性T细胞和IFN-γ诱导的PD-L1肿瘤细胞（TC），这预测了抗PD-1/L1治疗的高反应率。最近,CD161及其配体LLT1（CLEC2D）已被确定为免疫疗法的新兴检查点。明确其异质性临床表达模式及其免疫景观是在特定口腔鳞状细胞癌（OSCC）患者群体中最大化CD161阻断治疗的应答率的前提。这里,我们研究了CD161/LLT1的表达模式及其与主要免疫细胞(T细胞，B细胞,NK细胞,和巨噬细胞）通过多重免疫荧光，免疫组织化学，和流式细胞仪检测109个OSCC组织和102个外周血样本。TC显示LLT1水平高于肿瘤浸润淋巴细胞（TIL），而CD161在肿瘤前端的CD8+T细胞中高表达，在癌旁组织中减少。TC衍生的LLT1（LLT1TC）的高表达导致临床结局不佳，而较高的CD161+和LLT1+TIL与较好的预后相关。同时,高LLT1TC患者显示CD8+/Foxp3+T细胞的原位比例降低，但CD161+TIL与更多的外周CD3+T细胞相关。有趣的是,用纳武单抗（抗PD-1）治疗OSCC患者可以恢复肿瘤CD161/LLT1信号。此外，OSCC亚组的特点是高LLT1+TC和低CD161+CD8+T细胞显示较少的外周T细胞和较高的淋巴结转移风险，导致更短的5年生存时间（29％）。侵入性前沿的LLT1TC更多是耗尽T细胞的另一个风险特征。总之,鉴于这种异质性，应在基于CD161的免疫治疗之前确定LLT1/CD161的分布模式.
