title: Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma.
abstract: The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3(+) T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.
authors.affiliation: Department of Clinical Sciences and Services, Immune Regulation Laboratory, The Royal Veterinary College, London, United Kingdom.
authors.forename: Dammy
authors.initials: D
authors.lastname: Pinheiro
authors.affiliation: Research Office, The Royal Veterinary College, London, United Kingdom.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Chang
authors.affiliation: Department of Clinical Sciences and Services, Immune Regulation Laboratory, The Royal Veterinary College, London, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Bryant
authors.affiliation: Department of Pathology and Pathogen Biology, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Balazs
authors.initials: B
authors.lastname: Szladovits
authors.affiliation: Department of Clinical Sciences and Services, Immune Regulation Laboratory, The Royal Veterinary College, London, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Dalessandri
authors.affiliation: Henry Wellcome Building, Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom; Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Davison
authors.affiliation: Clinical Investigation Centre, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yallop
authors.affiliation: Clinical Investigation Centre, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Mills
authors.affiliation: Department of Clinical Sciences and Services, Queen Mother Hospital for Animals, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Chiara
authors.initials: C
authors.lastname: Leo
authors.affiliation: Department of Clinical Sciences and Services, Queen Mother Hospital for Animals, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Lara
authors.affiliation: Department of Clinical Sciences and Services, Queen Mother Hospital for Animals, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Anneliese
authors.initials: A
authors.lastname: Stell
authors.affiliation: Oncology Service, North Downs Specialist Referrals, Bletchingley, Surrey, United Kingdom.
authors.forename: Gerry
authors.initials: G
authors.lastname: Polton
authors.affiliation: Department of Clinical Sciences and Services, Immune Regulation Laboratory, The Royal Veterinary College, London, United Kingdom; Department of Clinical Sciences and Services, Queen Mother Hospital for Animals, The Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Garden
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology; D004285:Dogs; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis* / Q000276:immunology; D005802:Genes, MHC Class II; D051740:Ikaros Transcription Factor / Q000032:analysis / Q000276:immunology; D016130:Immunophenotyping; D016393:Lymphoma, B-Cell / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology / Q000662:veterinary*; D008297:Male; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; D051740:Ikaros Transcription Factor