Only a subset of patients responds to immune checkpoint blockade (ICB) in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti–mouse PD-L1 antibody similar to the anti–human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti–PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T-cell infiltration, and T-cell receptor (TCR) signatures in regressing tumors compared with tumors exhibiting no response to anti–PD-L1 treatment. We found that CD8+ T-cell tumor infiltration corresponded to response to treatment, and that anti–PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine–cytokine receptor interaction, and natural killer cell–mediated cytotoxicity. TCR sequence data suggest that an anti–PD-L1–mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy. Implications: Our melanoma model recapitulates the variable response to anti–PD-L1 observed in patients and exhibits biomarkers that characterize early antibody response, including expansion of the TCR repertoire.

中文翻译：

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不同的生物标志物谱和 TCR 序列多样性表征了小鼠黑色素瘤模型中对 PD-L1 阻断的反应

在黑色素瘤中，只有一部分患者对免疫检查点阻断 (ICB) 有反应。概括 ICB 临床活动的临床前模型将为机制研究提供有价值的平台。我们使用源自 Hgftg;Cdk4R24C/R24C 基因工程小鼠 (GEM) 模型的黑色素瘤肿瘤来评估类似于抗人 PD-L1 抗体 durvalumab 和 atezolizumab 的抗小鼠 PD-L1 抗体的功效。与黑色素瘤中 ICB 的临床观察结果一致，抗 PD-L1 治疗在一部分黑色素瘤小鼠中引发了完全和持久的反应。我们还观察到肿瘤生长延迟或消退，然后是复发。对于早期治疗评估，我们分析了基因表达谱、T 细胞浸润、与对抗 PD-L1 治疗无反应的肿瘤相比，肿瘤消退中的 T 细胞受体 (TCR) 特征。我们发现 CD8+ T 细胞肿瘤浸润对应于对治疗的反应，并且抗 PD-L1 基因特征反应表明抗原加工和呈递、细胞因子-细胞因子受体相互作用和自然杀伤细胞介导的细胞毒性增加。TCR 序列数据表明，抗 PD-L1 介导的黑色素瘤消退反应不仅需要扩大个体小鼠独有的 TCR 库，而且还需要肿瘤进入适当的 TCR。因此，这种黑色素瘤模型概括了在患者中观察到的对 ICB 的可变反应，并展示了区分早期反应和治疗抵抗的生物标志物，为预测成功的免疫治疗提供了一个有价值的平台。启示：我们的黑色素瘤模型概括了在患者中观察到的对抗 PD-L1 的可变反应，并展示了表征早期抗体反应的生物标志物，包括 TCR 库的扩展。