title: Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence.
abstract: Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFNγ+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous free-of-tumor renal tissues showed reduced T cell infiltrate and frequency of MAGE gene expression as compared to the autologous tumors. Importantly, the intra-tumor T effector/Treg cell ratio was consistently <1 in bladder cancer patients (n. 7) who relapsed within two years, while it was always >1 in patients (n. 6) without recurrence (regardless of tumor stage) (P = 0.0006, Odds ratio = 195). These unprecedented findings clarify the pathogenic mechanism of bladder cancer recurrence and suggest that microscopically undetectable micro-foci of tumor may predispose to recurrence when associated with an inverted intratumoral T effector/Treg cell ratio.
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Parodi
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.|Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Traverso
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Kalli
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Conteduca
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Tardito
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Curto
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Grillo
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bernardi
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Nasi
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Minaglia
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Alchiede
authors.initials: A
authors.lastname: Simonato
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carmignani
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrera
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.|Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fenoglio
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliero Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.|Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Filaci
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D058950:Melanoma-Specific Antigens / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: C072011:MAGEA1 protein, human; C574803:MageA2 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D012333:RNA, Messenger
keywords: Immune response; Immunity; Immunology and Microbiology Section; MAGE; Th1; Th17; bladder cancer; tumor infiltrating lymphocytes
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