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 K. Pierce 1 , Kathryn Mesh 1 , Steve Lianoglou 1 , Johannes Riegler 1 , Richard A. D. Carano 1 , Pontus Eriksson 2 , Mattias Hoglund 2 , Loan Somarriba 3 , Daniel L. Halligan 3 , Michiel 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
14 February 2018
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) 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 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.