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PMID: 28947544 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer immunology research ·Vol. 5 ·No. 11 ·2017-00-00 ·Pages 1005-1015

Colbeck EJ, Jones E, Hindley JP, Smart K, Schulz R, Browne M, Cutting S, Williams A, Parry L, Godkin A, Ware CF, Ager A, Gallimore A

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 that can increase frequencies of tumor-infiltrating lymphocytes through promoting the 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 coevolution 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 also 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 the TNF receptor and independent of lymphotoxin β receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model where 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. Cancer Immunol Res; 5(11); 1005-15. ©2017 AACR.

MeSH Terms
Animals Dendritic Cells/immunology Endothelium, Vascular/immunology Lymphocyte Depletion Lymphocytes, Tumor-Infiltrating/immunology Lymphotoxin beta Receptor/immunology Methylcholanthrene Mice Neoplasms/chemically induced,immunology Receptors, Tumor Necrosis Factor/immunology T-Lymphocytes, Regulatory/immunology
Chemicals
Lymphotoxin beta Receptor Receptors, Tumor Necrosis Factor Methylcholanthrene
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Colbeck Emily J
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK. e.colbeck@ucl.ac.uk.
Jones Emma
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Hindley James P
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Smart Kathryn
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Schulz Ralph
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Browne Molly
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Cutting Scott
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Williams Anwen
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Parry Lee
European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK.
Godkin Andrew
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Ware Carl F
Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, San Diego, California.
Ager Ann
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
Gallimore Awen
Division of Infection and Immunity, School of Medicine, SIURI, Cardiff University, Cardiff, UK.
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Article Info
Journal
Cancer immunology research
Abbr.
Cancer Immunol Res
ISSN
2326-6074
DOI
10.1158/2326-6066.CIR-17-0131
Email
e.colbeck@ucl.ac.uk
Published
2017-00-00
Epub
2017-00-25
Pages
1005-1015
Language
English
Region
United States
NLM ID
101614637
PMCID
PMC5668144
Subset
IM
Grants
Cancer Research UK · C16731/A21200 · United Kingdom
Wellcome Trust · 086983 · United Kingdom
Medical Research Council · MR/L008742/1 · United Kingdom
Wellcome Trust · United Kingdom
NCI NIH HHS · R01 CA164679 · United States
External Links
PubMed source DOI: 10.1158/2326-6066.CIR-17-0131 PMC Full Text View journal details
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