TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Journal Article

Authors: Mariathasan, S.; Turley, S. J.; Nickles, D.; Castiglioni, A.; Yuen, K.; Wang, Y.; Kadel, E. E. 3rd; Koeppen, H.; Astarita, J. L.; Cubas, R.; Jhunjhunwala, S.; Banchereau, R.; Yang, Y.; Guan, Y.; Chalouni, C.; Ziai, J.; Şenbabaoǧlu, Y.; Santoro, S.; Sheinson, D.; Hung, J.; Giltnane, J. M.; Pierce, A. A.; Mesh, K.; Lianoglou, S.; Riegler, J.; Carano, R. A. D.; Eriksson, P.; Höglund, M.; Somarriba, L.; Halligan, D. L.; van der Heijden, M. S.; Loriot, Y.; Rosenberg, J. E.; Fong, L.; Mellman, I.; Chen, D. S.; Green, M.; Derleth, C.; Fine, G. D.; Hegde, P. S.; Bourgon, R.; Powles, T.
Article Title: TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Abstract: 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. 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 β (TGFβ) 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 TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ 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 TGFβ shapes the tumour microenvironment to restrain anti-Tumour immunity by restricting T-cell infiltration. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Keywords: signal transduction; controlled study; human tissue; protein expression; overall survival; nonhuman; cd8+ t lymphocyte; tumor associated leukocyte; animal cell; mouse; animal tissue; gene; tumor volume; transforming growth factor beta; animal experiment; animal model; cohort analysis; tumor regression; urogenital tract cancer; regulatory t lymphocyte; cellular immunity; breast carcinoma; drug response; transforming growth factor beta1; fibroblast; cellular distribution; tumor immunity; effector cell; tumor growth; colon carcinoma; stroma cell; rna sequence; programmed death 1 ligand 1; mouse model; tumor microenvironment; transforming growth factor beta antibody; transforming growth factor beta receptor 2; clinical outcome; gamma interferon receptor 1; human; female; priority journal; article; tgfb1 gene; atezolizumab; acvr1 gene; ifngr1 gene; tgfbr2 gene
Journal Title: Nature
Volume: 554
Issue: 7693
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2018-02-22
Start Page: 544
End Page: 548
Language: English
DOI: 10.1038/nature25501
PROVIDER: scopus
PUBMED: 29443960
Notes: Article -- Export Date: 2 April 2018 -- Source: Scopus
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  1. Jonathan Eric Rosenberg
    227 Rosenberg