TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
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DOI：
10.1038/nature25501
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发表时间：
2018-02-22
期刊：
影响因子：
64.8
通讯作者：
Powles T
中科院分区：
文献类型：
--
作者：
Mariathasan S;Turley SJ;Nickles D;Castiglioni A;Yuen K;Wang Y;Kadel EE III;Koeppen H;Astarita JL;Cubas R;Jhunjhunwala S;Banchereau R;Yang Y;Guan Y;Chalouni C;Ziai J;Şenbabaoğlu Y;Santoro S;Sheinson D;Hung J;Giltnane JM;Pierce AA;Mesh K;Lianoglou S;Riegler J;Carano RAD;Eriksson P;Höglund M;Somarriba L;Halligan DL;van der Heijden MS;Loriot Y;Rosenberg JE;Fong L;Mellman I;Chen DS;Green M;Derleth C;Fine GD;Hegde PS;Bourgon R;Powles T
阻断程序性死亡配体1（PD-L1）/程序性死亡-1（PD-1）途径的治疗性抗体可在患有各种癌症（包括转移性尿路上皮癌（mUC））的患者中诱导稳健且持久的应答。然而，这些反应仅发生在一部分患者中。阐明反应和耐药性的决定因素是改善结果和开发新治疗策略的关键。在这里，我们检查了一个大型mUC患者队列的肿瘤，这些患者接受抗PD-L1药物（atezolizumab）治疗，并确定了临床结局的主要决定因素。缓解与CD 8 + T效应细胞表型相关，甚至在更大程度上与高新抗原或肿瘤突变负荷（TMB）相关。缺乏反应与成纤维细胞中转化生长因子β（TGF-β）信号传导的特征相关，特别是在CD 8 + T细胞从肿瘤实质中排除，而是在富含成纤维细胞和胶原蛋白的瘤周基质中发现的患者中-这是mUC患者中的常见表型。使用重现这种免疫排斥表型的小鼠模型，我们发现TGF-β阻断抗体与抗PD-L1一起治疗性给药减少了基质细胞中的TGF-β信号传导，促进了T细胞渗透到肿瘤中心，并引发了强烈的抗肿瘤免疫和肿瘤消退。这三个独立的生物学特征的整合为理解这种情况下的结果提供了最佳基础，并表明TGF-β通过限制T细胞浸润来塑造肿瘤微环境以抑制抗肿瘤免疫。
Therapeutic antibodies that block the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer (mUC). 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 mUC patients treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). Lack of response was associated with a signature of transforming growth factor β (TGF-β) signalling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from the tumour parenchyma and instead found in the fibroblast- and collagen-rich peritumoural stroma—a common phenotype among patients with mUC. Using a mouse model that recapitulates this immune excluded phenotype, we found that therapeutic administration of a TGF-β blocking antibody together with anti–PD-L1 reduced TGF-β signalling in stromal cells, facilitated T cell penetration into the centre of the tumour, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding outcome in this setting and suggests that TGF-β shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T cell infiltration.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
转化生长因子-β在癌症中作用的机制基础和临床相关性
影响因子：
5.5
作者：
Lin RL;Zhao LJ
通讯作者：
Zhao LJ
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
DOI：
10.1016/s0140-6736(16)00561-4
发表时间：
2016-05-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Rosenberg JE;Hoffman-Censits J;Powles T;van der Heijden MS;Balar AV;Necchi A;Dawson N;O'Donnell PH;Balmanoukian A;Loriot Y;Srinivas S;Retz MM;Grivas P;Joseph RW;Galsky MD;Fleming MT;Petrylak DP;Perez-Gracia JL;Burris HA;Castellano D;Canil C;Bellmunt J;Bajorin D;Nickles D;Bourgon R;Frampton GM;Cui N;Mariathasan S;Abidoye O;Fine GD;Dreicer R
通讯作者：
Dreicer R