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Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Destruction

Colbeck, EJ; Jones, E; Hindley, JP; Smart, K; Schulz, R; Browne, M; Cutting, S; ... Gallimore, A; + view all (2017) Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Destruction. Cancer Immunology Research , 5 (11) 10.1158/2326-6066.CIR-17-0131. Green open access

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Abstract

T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process which can increase frequencies of tumor-infiltrating lymphocytes (TILs) through promoting development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model, that allows for co-evolution of the tumor microenvironment and the immune response, to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on TNF receptor and independent of lymphotoxin beta receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model whereby Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer.

Type: Article
Title: Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Destruction
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/2326-6066.CIR-17-0131
Publisher version: https://doi.org/10.1158/2326-6066.CIR-17-0131
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/10022740
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