title: Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.
abstract: The tumor microenvironment comprises newly formed blood and lymphatic vessels which shape the influx, retention and departure of lymphocytes within the tumor mass. Thus, by influencing the intratumoral composition of lymphocytes, these vessels affect the manner in which the adaptive immune system responds to the tumor, either promoting or impairing effective antitumor immunity. In our study, we utilized a mouse model of carcinogen-induced fibrosarcoma to examine the composition of tumor-infiltrating lymphocytes during tumor progression. In particular, we sought to determine whether CD4(+) Foxp3(+) regulatory T cells (Tregs) became enriched during tumor progression thereby contributing to tumor-driven immunosuppression. This was not the case as the proportion of Tregs and effector CD4(+) T cells actually declined within the tumor owing to the unexpected accumulation of naïve T cells. However, we found no evidence for antigen-driven migration of these T cells or for their participation in an antitumor immune response. Our data support the notion that lymphocytes can enter tumors via aberrantly formed blood and lymphatic vessels. Such findings suggest that targeting both the tumor vasculature and lymphatics will alter the balance of lymphocyte subpopulations that enter the tumor mass. A consideration of this aspect of tumor immunology may be critical to the success of solid cancer immunotherapies.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Ondondo
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.forename: James
authors.initials: J
authors.lastname: Hindley
authors.forename: Scott
authors.initials: S
authors.lastname: Cutting
authors.forename: Kathryn
authors.initials: K
authors.lastname: Smart
authors.forename: Hayley
authors.initials: H
authors.lastname: Bridgeman
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthews
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
authors.forename: Andrew
authors.initials: A
authors.lastname: Godkin
authors.forename: Ann
authors.initials: A
authors.lastname: Ager
authors.forename: Awen
authors.initials: A
authors.lastname: Gallimore
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002273:Carcinogens / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D002273:Carcinogens
keywords: T cells; carcinogen; lymphatics