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

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.

journal_name

Nature

journal_title

Nature

authors

Mariathasan S,Turley SJ,Nickles D,Castiglioni A,Yuen K,Wang Y,Kadel EE III,Koeppen H,Astarita JL,Cubas R,Jhunjhunwala S,Banchereau R,Yang Y,Guan Y,Chalouni C,Ziai J,Şenbabaoğlu Y,Santoro S,Sheinson D,Hung J,Giltna

doi

10.1038/nature25501

subject

Has Abstract

pub_date

2018-02-22 00:00:00

pages

544-548

issue

7693

eissn

0028-0836

issn

1476-4687

pii

nature25501

journal_volume

554

pub_type

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