树突状细胞效应机制和肿瘤免疫微环境浸润决定了 TLR8 调控和 PD-1 阻断剂的作用

Daniel A Ruiz Torres, Jillian Wise, Brian Zhao, Joao P Oliveira-Costa, Sara Cavallaro, Peter Sadow, Jacy Fang, Osman Yilmaz, Amar Patel, Christopher Loosbroock, Moshe Sade-Feldman, Daniel L Faden, Shannon L Stott
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摘要

收费样受体 8(TLR8)激动剂与 PD-1 阻断剂联合使用可产生强大的免疫刺激效应,临床前研究对此进行了多种研究,但其在人体中的作用机制仍然未知。为了破解 TLR8 激动剂与 PD-1 阻断剂的联合作用模式,我们在头颈部鳞状细胞癌(HNSCC)患者中开展了一项独特的、开放标签的 1b 期术前机会之窗临床试验(NCT03906526)。我们从同一病灶获取了治疗前和治疗后匹配的肿瘤活检样本。我们利用单细胞 RNA 测序和定制的多重染色技术,发挥同病灶纵向取样的独特优势。接受TLR8激动剂和抗PD-1阻断剂双重治疗的患者表现出先天性免疫效应基因和细胞因子的明显上调,突出表现为CLEC9A+树突状细胞和CLEC7A/SYK表达的增加。通过与之前抗PD-1阻断单药治疗单细胞RNA测序研究的队列进行比较,发现了这一点。此外,在双重疗法患者中,治疗后成熟树突状细胞与CD8+ T细胞的毗邻关系增加。在应答者中观察到肿瘤细胞毒性T淋巴细胞密度增加,CXCL13+CD8+ T细胞群扩大,所有三名患者的三级淋巴结构(TLS)都有所增加。这项研究为了解TLR8激动和抗PD-1阻断免疫靶向在HNSCC患者中的作用模式提供了重要见解。
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Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade
The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8+ T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+ T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.
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