title: Sialyl Tn-expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells.
abstract: Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how they contribute to the tilt immune response remains poorly defined. In this study, we sought to evaluate the impact of the malignant phenotype-associated glycan, sialyl-Tn (STn) in the function of the key orchestrators of the immune response, the dendritic cells (DCs). In high grade bladder cancer tissue, the STn antigen is significantly overexpressed and correlated with the increased expression of ST6GALNAC1 sialyltransferase. Bladder cancer tissue presenting elevated expression of ST6GALNAC1 showed a correlation with increased expression of CD1a, a marker for bladder immature DCs and showed concomitant low levels of Th1-inducing cytokines IL-12 and TNF-α. In vitro, human DCs co-incubated with STn(+) bladder cancer cells, had an immature phenotype (MHC-II(low), CD80(low) and CD86(low)) and were unresponsive to further maturation stimuli. When contacting with STn(+) cancer cells, DCs expressed significantly less IL-12 and TNF-α. Consistent with a tolerogenic DC profile, T cells that were primed by DCs pulsed with antigens derived from STn(+) cancer cells were not activated and showed a FoxP3(high) IFN-γ(low) phenotype. Blockade of STn antigens and of STn(+) glycoprotein, CD44 and MUC1, in STn(+) cancer cells was able to lower the induction of tolerance and DCs become more mature. Overall, our data suggest that STn-expressing cancer cells impair DC maturation and endow DCs with a tolerogenic function, limiting their capacity to trigger protective anti-tumour T cell responses. STn antigens and, in particular, STn(+) glycoproteins are potential targets for circumventing tumour-induced tolerogenic mechanisms.
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
authors.forename: Mylène A
authors.initials: MA
authors.lastname: Carrascal
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal; Department of Experimental, Clinical and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Paulo F
authors.initials: PF
authors.lastname: Severino
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal; Faculdade de Engenharia, Universidade Lusófona de Humanidades e Tecnologias, Lisbon, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Guadalupe Cabral
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Silva
authors.affiliation: QOPNA, Mass Spectrometry Center, Department of Chemistry, University of Aveiro, Aveiro, Portugal; Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: José Alexandre
authors.initials: JA
authors.lastname: Ferreira
authors.affiliation: Centro Hospitalar de Lisboa Central, EPE - Serviço de Anatomia Patológica, Lisbon, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calais
authors.affiliation: Centro Hospitalar de Lisboa Central, EPE - Serviço de Anatomia Patológica, Lisbon, Portugal.
authors.forename: Hermínia
authors.initials: H
authors.lastname: Quinto
authors.affiliation: Centro Hospitalar de Lisboa Central, EPE - Serviço de Anatomia Patológica, Lisbon, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Pen
authors.affiliation: Centro de Histocompatibilidade do Sul, Lisboa, Portugal.
authors.forename: Dário
authors.initials: D
authors.lastname: Ligeiro
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal; Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Lúcio Lara
authors.initials: LL
authors.lastname: Santos
authors.affiliation: Department of Experimental, Clinical and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Dall'Olio
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal. Electronic address: paula.videira@fcm.unl.pt.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Videira
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000032:analysis / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000276:immunology; D007113:Immunity, Innate; D008875:Middle Aged; D010587:Phagocytosis; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001743:Urinary Bladder / Q000276:immunology / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000473:pathology
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D018960:Hyaluronan Receptors; C055491:sialosyl-Tn antigen
keywords: CD44; Dendritic cells; Immunological potency; Mucins; Sialyl-Tn; T cells