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EOH Journal Club - Spring 2018 - Travis Lear

Thursday 4/5 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room
EOH Journal Club Seminar - Spring 2018

Date: Thursday April 5, 2018

Time: 11am - 12pm

Presenter: Travis Lear

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

Authors: Sanjeev Mariathasan, Shannon J. Turley[…]Thomas Powles

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 cancer1,2,3,4,5. 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 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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Last Updated On Thursday, February 22, 2018 by Orbell, Adam W
Created On Thursday, February 22, 2018

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