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

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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.

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:	18 Nov 2024 08:00
URI:	https://orca.cardiff.ac.uk/id/eprint/105183

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