Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction

Colbeck, Emily J., Jones, Emma, Hindley, James P., Smart, Kathryn, Schulz, Ralph, Browne, Molly, Cutting, Scott, Williams, Anwen ORCID: https://orcid.org/0000-0001-6118-020X, Parry, Lee ORCID: https://orcid.org/0000-0002-4467-9196, Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567, Ware, Carl F., Ager, Ann and Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 2017. Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction. Cancer Immunology Research 5 (11) , pp. 1005-1015. 10.1158/2326-6066.CIR-17-0131

[thumbnail of Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Deletion - Lee Parry.pdf]
Preview
PDF - Accepted Post-Print Version
Download (1MB) | Preview

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Medicine
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: R Medicine > R Medicine (General)
Publisher: American Association for Cancer Research
ISSN: 2326-6066
Date of First Compliant Deposit: 10 October 2017
Date of Acceptance: 18 September 2017
Last Modified: 12 Nov 2023 02:15
URI: https://orca.cardiff.ac.uk/id/eprint/105183

Citation Data

Cited 54 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics