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

Mariathasan, Sanjeev; Turley, Shannon J.; Nickles, Dorothee; Castiglioni, Alessandra; Yuen, Kobe; Wang, Yulei; Kadel, Edward E.; Koeppen, Hartmut; Astarita, Jillian L. and Cubas, Rafael, et al. (2018) In Nature 554(7693). p.544-548
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... (More)

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.

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@article{eafb86a6-8810-4b93-8882-732363b8ff58,
  abstract     = {<p>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.</p>},
  author       = {Mariathasan, Sanjeev and Turley, Shannon J. and Nickles, Dorothee and Castiglioni, Alessandra and Yuen, Kobe and Wang, Yulei and Kadel, Edward E. and Koeppen, Hartmut and Astarita, Jillian L. and Cubas, Rafael and Jhunjhunwala, Suchit and Banchereau, Romain and Yang, Yagai and Guan, Yinghui and Chalouni, Cecile and Ziai, James and Şenbabaoǧlu, Yasin and Santoro, Stephen and Sheinson, Daniel and Hung, Jeffrey and Giltnane, Jennifer M. and Pierce, Andrew A. and Mesh, Kathryn and Lianoglou, Steve and Riegler, Johannes and Carano, Richard A.D. and Eriksson, Pontus and Höglund, Mattias and Somarriba, Loan and Halligan, Daniel L. and Van Der Heijden, Michiel S. and Loriot, Yohann and Rosenberg, Jonathan E. and Fong, Lawrence and Mellman, Ira and Chen, Daniel S. and Green, Marjorie and Derleth, Christina and Fine, Gregg D. and Hegde, Priti S. and Bourgon, Richard and Powles, Thomas},
  issn         = {0028-0836},
  language     = {eng},
  month        = {02},
  number       = {7693},
  pages        = {544--548},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells},
  url          = {http://dx.doi.org/10.1038/nature25501},
  volume       = {554},
  year         = {2018},
}