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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Sanjeev Mariathasan
  • Shannon J. Turley
  • Dorothee Nickles
  • Alessandra Castiglioni
  • Kobe Yuen
  • Yulei Wang
  • Edward E. Kadel
  • Hartmut Koeppen
  • Jillian L. Astarita
  • Rafael Cubas
  • Suchit Jhunjhunwala
  • Romain Banchereau
  • Yagai Yang
  • Yinghui Guan
  • Cecile Chalouni
  • James Ziai
  • Yasin Şenbabaoǧlu
  • Stephen Santoro
  • Daniel Sheinson
  • Jeffrey Hung
  • Jennifer M. Giltnane
  • Andrew A. Pierce
  • Kathryn Mesh
  • Steve Lianoglou
  • Johannes Riegler
  • Richard A.D. Carano
  • Loan Somarriba
  • Daniel L. Halligan
  • Michiel S. Van Der Heijden
  • Yohann Loriot
  • Jonathan E. Rosenberg
  • Lawrence Fong
  • Ira Mellman
  • Daniel S. Chen
  • Marjorie Green
  • Christina Derleth
  • Gregg D. Fine
  • Priti S. Hegde
  • Richard Bourgon
  • Thomas Powles
Enheter & grupper
Externa organisationer
  • Fios Genomics
  • Netherlands Cancer Institute
  • University of Paris-Sud
  • Memorial Sloan-Kettering Cancer Center
  • UCSF Helen Diller Family Comprehensive Cancer Center
  • Queen Mary University
  • Genentech, Inc
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)544-548
Antal sidor5
TidskriftNature
Volym554
Utgivningsnummer7693
StatusPublished - 2018 feb 22
PublikationskategoriForskning
Peer review utfördJa