Characterization of the Immune Response to PD-1 Blockade during Chemoradiotherapy for Head and Neck Squamous Cell Carcinoma.
Characterization of the Immune Response to PD-1 Blockade during Chemoradiotherapy for Head and Neck Squamous Cell Carcinoma.
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PD-1/L1相互作用的阻断代表了复发性/转移性头颈部鳞状细胞癌（HNSCC）治疗的突破。临床和转化研究表明，这种相互作用可能在放化疗期间的免疫逃避中发挥作用。使用HNSCC的免疫活性鼠模型，我们证明了PD-1阻断与基于顺铂的同步放化疗的改善的功效。将这种方法应用于评估抗PD-1药物pembrolizumab联合放化疗治疗HNSCC的临床试验，我们表征了外周血对治疗的免疫应答。我们的研究结果强调，这种组合在小鼠模型中具有活性，并且在临床试验期间循环PD-1+ T细胞比例降低。然而，来自临床试验的其他发现表明向免疫衰竭的其他标志物的表达转变。由于这种治疗方法正在大型随机试验中进行探索，这些发现为治疗失败的潜在途径提供了见解。背景：放化疗是HNSCC的标准治疗方法。PD-1/L1-2相互作用的阻断可能代表在该治疗期间克服免疫逃逸的目标。方法：利用HNSCC mEERL C57 BL/6小鼠模型，我们评估了PD-1阻断单独或与基于顺铂的放化疗组合。接下来，我们评估了具有相对PD-1、TIM-3和LAG-3表达的外周血单核细胞（PBMC），以及来自评估HNSCC中的PD-1阻断与放化疗的临床试验的髓源性抑制因子样（MDSC样）群体。最后，我们通过T细胞受体（TCR）测序分析了治疗对人类T细胞克隆性的影响。结果如下：抗PD-1单药治疗在mEERL模型中未诱导应答;然而，与放化疗联合治疗可改善肿瘤清除率和存活率。来自接受该联合疗法治疗的患者的PBMC显示循环T细胞群下降，治疗期间表达PD-1的CD 3 + CD 4+和CD 3 + CD 8 + T细胞被敲低。然而，表达TIM-3、LAG-3的T细胞和MDSC样群体一致上升。在治疗期间，TCR库显示出整体克隆扩增，具有独特的和先前报道的T细胞克隆。结论：我们的鼠HNSCC模型证明了在放化疗期间PD-1阻断的有效性。然而，虽然表达PD-1的T细胞在这种治疗中减少，但人类PBMC的发现也发现了导致免疫衰竭的群体增加。这些发现进一步表征了HNSCC放化疗期间的PD-1阻断，并强调了免疫逃避的潜在竞争机制。
Blockade of the PD-1/L1 interaction represents a breakthrough in the treatment for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Clinical and translational research suggests that this interaction may play a role in immune evasion during chemoradiotherapy. Using an immune-competent murine model of HNSCC, we demonstrate improved efficacy of PD-1 blockade with concurrent cisplatin-based chemoradiotherapy. Taking this approach into a clinical trial evaluating the anti-PD-1 agent, pembrolizumab, combined with chemoradiotherapy in HNSCC, we characterized the peripheral blood immune response to therapy. Our findings highlight that this combination is active in the murine model and circulating PD-1+ T-cell proportions were decreased during the clinical trial. However, additional findings from the clinical trial suggest a shift towards expression of other markers of immune exhaustion. As this treatment approach is being explored in large, randomized trials, these findings provide insight into potential pathways for treatment failure. Background: Chemoradiotherapy is a standard treatment for HNSCC. Blockade of the PD-1/L1-2 interaction may represent a target to overcome immune escape during this treatment. Methods: Utilizing a HNSCC mEERL C57BL/6 mouse model, we evaluated a PD-1 blockade alone or in combination with cisplatin-based chemoradiotherapy. Next, we evaluated peripheral blood mononuclear cells (PBMCs) with relative PD-1, TIM-3, and LAG-3 expression, and myeloid-derived suppressor-like (MDSC-like) populations from a clinical trial evaluating PD-1 blockade with chemoradiotherapy in HNSCC. Finally, we analyzed the effect of therapy on human T-cell clonality through T-cell Receptor (TCR) sequencing. Results: Anti-PD-1 monotherapy induced no response in the mEERL model; however, combination with chemoradiotherapy improved tumor clearance and survival. PBMCs from patients treated with this combination therapy demonstrate a decline in circulating T-cell populations with knockdown of PD-1 expressing CD3+CD4+ and CD3+CD8+ T cells during treatment. However, TIM-3, LAG-3 expressing T-cell and MDSC-like populations concordantly rose. During treatment, the TCR repertoire demonstrates overall clonal expansion, with both unique and previously reported T-cell clones. Conclusions: Our murine HNSCC model demonstrates efficacy of PD-1 blockade during chemoradiotherapy. However, while PD-1-expressing T cells decreased with this therapy, human PBMC findings also identified an increase in populations contributing to immune exhaustion. These findings further characterize PD-1 blockade during chemoradiotherapy for HNSCC and highlight potential competing mechanisms of immune evasion.
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TIM-3 表达是肿瘤组织中调节性 T 细胞的特征，并与肺癌进展相关
影响因子：
3.7
作者：
Gao X;Zhu Y;Li G;Huang H;Zhang G;Wang F;Sun J;Yang Q;Zhang X;Lu B
通讯作者：
Lu B
影响因子：
11.2
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通讯作者：
Pai SI
DOI：
10.1158/1078-0432.ccr-18-1038
发表时间：
2018-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Oweida A;Hararah MK;Phan A;Binder D;Bhatia S;Lennon S;Bukkapatnam S;Van Court B;Uyanga N;Darragh L;Kim HM;Raben D;Tan AC;Heasley L;Clambey E;Nemenoff R;Karam SD
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Karam SD
DOI：
10.1056/nejmoa0912217
发表时间：
2010-07-01
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ang KK;Harris J;Wheeler R;Weber R;Rosenthal DI;Nguyen-Tân PF;Westra WH;Chung CH;Jordan RC;Lu C;Kim H;Axelrod R;Silverman CC;Redmond KP;Gillison ML
通讯作者：
Gillison ML
影响因子：
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作者：
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