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

  • Nature. 2018 Feb 22;554(7693):544-548. doi: 10.1038/nature25501.
Sanjeev Mariathasan  1 ,  Shannon J Turley  1 ,  Dorothee Nickles  1 ,  Alessandra Castiglioni  1 ,  Kobe Yuen  1 ,  Yulei Wang  1 ,  Edward E Kadel III  1 ,  Hartmut Koeppen  1 ,  Jillian L Astarita  1 ,  Rafael Cubas  1 ,  Suchit Jhunjhunwala  1 ,  Romain Banchereau  1 ,  Yagai Yang  1 ,  Yinghui Guan  1 ,  Cecile Chalouni  1 ,  James Ziai  1 ,  Yasin Şenbabaoğlu  1 ,  Stephen Santoro  1 ,  Daniel Sheinson  1 ,  Jeffrey Hung  1 ,  Jennifer M Giltnane  1 ,  Andrew A Pierce  1 ,  Kathryn Mesh  1 ,  Steve Lianoglou  1 ,  Johannes Riegler  1 ,  Richard A D Carano  1 ,  Pontus Eriksson  2 ,  Mattias Höglund  2 ,  Loan Somarriba  3 ,  Daniel L Halligan  3 ,  Michiel S van der Heijden  4 ,  Yohann Loriot  5 ,  Jonathan E Rosenberg  6 ,  Lawrence Fong  7 ,  Ira Mellman  1 ,  Daniel S Chen  1 ,  Marjorie Green  1 ,  Christina Derleth  1 ,  Gregg D Fine  1 ,  Priti S Hegde  1 ,  Richard Bourgon  1 ,  Thomas Powles  8
Affiliations
  • 1. Genentech, South San Francisco, California 94080, USA.
  • 2. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Skåne 223 81, Sweden.
  • 3. Fios Genomics, Edinburgh EH16 4UX, UK.
  • 4. Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
  • 5. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 94800 Villejuif, France.
  • 6. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 7. University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94158, USA.
  • 8. Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
PMID: 29443960 DOI: 10.1038/nature25501
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.