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

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

Mariathasan, Sanjeev (author): Genentech, Inc

Turley, Shannon J. (author): Genentech, Inc

Nickles, Dorothee (author): Genentech, Inc

Castiglioni, Alessandra (author): Genentech, Inc

Yuen, Kobe (author): Genentech, Inc

Wang, Yulei (author): Genentech, Inc

Kadel, Edward E. (author): Genentech, Inc

Koeppen, Hartmut (author): Genentech, Inc

Astarita, Jillian L. (author): Genentech, Inc

Cubas, Rafael (author): Genentech, Inc

Jhunjhunwala, Suchit (author): Genentech, Inc

Banchereau, Romain (author): Genentech, Inc

Yang, Yagai (author): Genentech, Inc

Guan, Yinghui (author): Genentech, Inc

Chalouni, Cecile (author): Genentech, Inc

Ziai, James (author): Genentech, Inc

Şenbabaoǧlu, Yasin (author): Genentech, Inc

Santoro, Stephen (author): Genentech, Inc

Sheinson, Daniel (author): Genentech, Inc

Hung, Jeffrey (author): Genentech, Inc

Giltnane, Jennifer M. (author): Genentech, Inc

Pierce, Andrew A. (author): Genentech, Inc

Mesh, Kathryn (author): Genentech, Inc

Lianoglou, Steve (author): Genentech, Inc

Riegler, Johannes (author): Genentech, Inc

Carano, Richard A.D. (author): Genentech, Inc

Eriksson, Pontus (author): Lund University,Lunds universitet,Genomiska analyser av urinblåscancer,Forskargrupper vid Lunds universitet,Urothelial Cancer Genomics,Lund University Research Groups

Höglund, Mattias (author): Lund University,Lunds universitet,Genomiska analyser av urinblåscancer,Forskargrupper vid Lunds universitet,Urothelial Cancer Genomics,Lund University Research Groups

Somarriba, Loan (author): Fios Genomics

Halligan, Daniel L. (author): Fios Genomics

Van Der Heijden, Michiel S. (author): Netherlands Cancer Institute

Loriot, Yohann (author): University of Paris-Saclay

Rosenberg, Jonathan E. (author): Memorial Sloan-Kettering Cancer Center

Fong, Lawrence (author): UCSF Helen Diller Family Comprehensive Cancer Center

Mellman, Ira (author): Genentech, Inc

Chen, Daniel S. (author): Genentech, Inc

Green, Marjorie (author): Genentech, Inc

Derleth, Christina (author): Genentech, Inc

Fine, Gregg D. (author): Genentech, Inc

Hegde, Priti S. (author): Genentech, Inc

Bourgon, Richard (author): Genentech, Inc

Powles, Thomas (author): Queen Mary University

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(creator_code:org_t)

2018-02-14
2018
English 5 s.
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 554:7693, s. 544-548

Related links:: http://dx.doi.org/10...; show more...; https://europepmc.or...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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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By the author/editor: Mariathasan, San ...; Turley, Shannon ...; Nickles, Dorothe ...; Castiglioni, Ale ...; Yuen, Kobe; Wang, Yulei; show more...; Kadel, Edward E.; Koeppen, Hartmut; Astarita, Jillia ...; Cubas, Rafael; Jhunjhunwala, Su ...; Banchereau, Roma ...; Yang, Yagai; Guan, Yinghui; Chalouni, Cecile; Ziai, James; Şenbabaoǧlu, Yas ...; Santoro, Stephen; Sheinson, Daniel; Hung, Jeffrey; Giltnane, Jennif ...; Pierce, Andrew A ...; Mesh, Kathryn; Lianoglou, Steve; Riegler, Johanne ...; Carano, Richard ...; Eriksson, Pontus; Höglund, Mattias; Somarriba, Loan; Halligan, Daniel ...; Van Der Heijden, ...; Loriot, Yohann; Rosenberg, Jonat ...; Fong, Lawrence; Mellman, Ira; Chen, Daniel S.; Green, Marjorie; Derleth, Christi ...; Fine, Gregg D.; Hegde, Priti S.; Bourgon, Richard; Powles, Thomas; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

Articles in the publication: Nature

By the university: Lund University

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

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