Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer

Mélanie Desbois, Akshata R. Udyavar, Lisa Ryner, Cleopatra Kozlowski, Yinghui Guan, Milena Dürrbaum, Shan Lu, Jean-Philippe Fortin, Hartmut Koeppen, James Ziai, Ching-Wei Chang, Shilpa Keerthivasan, Marie Plante, Richard Bourgon, Carlos Bais, Priti Hegde, Anneleen Daemen, Shannon Turley and Yulei Wang ()
Additional contact information
Mélanie Desbois: Genentech, Inc.
Akshata R. Udyavar: Genentech, Inc.
Lisa Ryner: Genentech, Inc.
Cleopatra Kozlowski: Genentech, Inc.
Yinghui Guan: Genentech, Inc.
Milena Dürrbaum: Genentech, Inc.
Shan Lu: Genentech, Inc.
Jean-Philippe Fortin: Genentech, Inc.
Hartmut Koeppen: Genentech, Inc.
James Ziai: Genentech, Inc.
Ching-Wei Chang: Genentech, Inc.
Shilpa Keerthivasan: Genentech, Inc.
Marie Plante: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec
Richard Bourgon: Genentech, Inc.
Carlos Bais: Genentech, Inc.
Priti Hegde: Genentech, Inc.
Anneleen Daemen: Genentech, Inc.
Shannon Turley: Genentech, Inc.
Yulei Wang: Genentech, Inc.

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. Furthermore, we identify TGFβ as an important mediator of T cell exclusion. TGFβ reduces MHC-I expression in ovarian cancer cells in vitro. TGFβ also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFβ might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19408-2

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DOI: 10.1038/s41467-020-19408-2

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