title: T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion.
abstract: The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T-cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy.
authors.affiliation: Infection and Immunity, School of Medicine, Henry Wellcome Building, Cardiff University, Cardiff, United Kingdom.
authors.forename: James P
authors.initials: JP
authors.lastname: Hindley
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.forename: Kathryn
authors.initials: K
authors.lastname: Smart
authors.forename: Hayley
authors.initials: H
authors.lastname: Bridgeman
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Lauder
authors.forename: Beatrice
authors.initials: B
authors.lastname: Ondondo
authors.forename: Scott
authors.initials: S
authors.lastname: Cutting
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Wynn
authors.forename: David
authors.initials: D
authors.lastname: Withers
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Ann
authors.initials: A
authors.lastname: Ager
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Godkin
authors.forename: Awen M
authors.initials: AM
authors.lastname: Gallimore
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D014699:Venules / Q000276:immunology*