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首页> 外文期刊>Nature >TGF beta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
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TGF beta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

机译：TGFβ通过排除T细胞而减弱了对PD-L1阻断的肿瘤反应

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摘要

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer(1-5). However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8(+) T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor beta (TGF beta) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8(+) T cells from the tumour parenchyma that were instead found in the fibroblast-and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGF beta-blocking and anti-PD-L1 antibodies reduced TGF beta signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGF beta shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.
机译：阻断程序性死亡1（PD-1）-程序性死亡配体1（PD-L1）通路的治疗性抗体可以在包括转移性尿路上皮癌在内的各种癌症患者中诱导强大而持久的反应（1-5）。但是，这些反应仅发生在一部分患者中。阐明反应和抵抗力的决定因素是改善疗效和制定新治疗策略的关键。在这里，我们检查了一大批转移性尿路上皮癌患者的肿瘤，这些患者接受了抗PD-L1药物（atezolizumab）治疗，并确定了临床结果的主要决定因素。对治疗的反应与CD8（+）T效应细胞表型有关，更大程度上与高新抗原或肿瘤突变负担有关。缺乏反应与成纤维细胞中转化生长因子β（TGF beta）信号转导的信号有关。这种情况尤其发生在患有肿瘤的患者中，这些患者显示出从肿瘤实质中排除了CD8（+）T细胞，而CD8（+）T细胞则在富含成纤维细胞和胶原蛋白的肿瘤周围基质中被发现。在转移性尿路上皮癌患者中常见的表型。我们使用小鼠模型概括了这种免疫排斥的表型，我们发现TGFβ受体阻滞剂和抗PD-L1抗体的治疗性共用减少了基质细胞中TGFβ的信号传导，促进T细胞穿透进入肿瘤中心，并激发了强大的抗肿瘤免疫力和肿瘤消退。这三个独立的生物学特征的整合为了解这种情况下的患者预后提供了最好的基础，并暗示TGFβ可通过限制T细胞浸润来塑造肿瘤微环境，从而抑制抗肿瘤免疫力。

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