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

ABSTRACT: We examined tumours from a large cohort of patients with metastatic urothelial bladder cancer (mUC) treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical response and immune escape. Whole transcriptome profiles were generated for 368 patients using TruSeq RNA Access technology (Illumina). Somatic mutations were determined via whole exome sequencing for a subset of these patients. - Response was associated with CD8+ T effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). On the other hand, lack of response was associated with a transforming growth factor β (TGF-β) signature, particularly in patients with CD8+ T cells preferentially residing in collagen-rich matrix surrounding tumours. Integration of these three independent biological features provided the best basis for understanding outcome in this setting. -

PROVIDER: EGAS00001002556 | EGA |

REPOSITORIES: EGA

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

Mariathasan Sanjeev S   Turley Shannon J SJ   Nickles Dorothee D   Castiglioni Alessandra A   Yuen Kobe K   Wang Yulei Y   Kadel Edward E EE   Koeppen Hartmut H   Astarita Jillian L JL   Cubas Rafael R   Jhunjhunwala Suchit S   Banchereau Romain R   Yang Yagai Y   Guan Yinghui Y   Chalouni Cecile C   Ziai James J   Şenbabaoğlu Yasin Y   Santoro Stephen S   Sheinson Daniel D   Hung Jeffrey J   Giltnane Jennifer M JM   Pierce Andrew A AA   Mesh Kathryn K   Lianoglou Steve S   Riegler Johannes J   Carano Richard A D RAD   Eriksson Pontus P   Höglund Mattias M   Somarriba Loan L   Halligan Daniel L DL   van der Heijden Michiel S MS   Loriot Yohann Y   Rosenberg Jonathan E JE   Fong Lawrence L   Mellman Ira I   Chen Daniel S DS   Green Marjorie M   Derleth Christina C   Fine Gregg D GD   Hegde Priti S PS   Bourgon Richard R   Powles Thomas T  

Nature 20180214 7693

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 wh  ...[more]

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