PDF(Pubmed)
Abstract：
The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.
摘要：
放疗/放化疗和免疫检查点阻断的组合可导致局部晚期头颈部鳞状细胞癌（HNSCC）患者的不良预后。这里,我们表明，ATR抑制（ATRi）与放疗（RT）联合使用会增加HNSCC动物模型中激活的NKG2APD-1T细胞的频率。与单独的ATRi/RT治疗方案相比，在ATRi/RT中同时添加NKG2A和PD-L1阻断，在佐剂中，放疗后设置诱导由肿瘤微环境中细胞毒性T细胞的更高浸润和活化驱动的强大抗肿瘤反应。这种组合的疗效依赖于CD40/CD40L共刺激和浸润的活化，增殖记忆CD8+和CD4+T细胞持续或新的T细胞受体（TCR）信号，分别。我们还观察到TCR库的丰富度增加，以及基于对NKG2A/PD-L1/ATRi/RT的抗原特异性聚集的大量和大型TCR克隆型的出现。总的来说，我们的数据指向治疗HNSCC的潜在组合方法.
