title: Intra-tumoral IFN-γ-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer.
abstract: PDAC (pancreatic ductal adenocarcinoma) is the fifth leading cause of cancer-related death. The causes of this cancer remain unknown, but increasing evidence indicates a key role of the host immune response and cytokines in human carcinogenesis. Intra-tumoral IL (interleukin)-22 levels have been shown to be elevated in PDAC patients. However, little is known regarding the expression and clinical relevance of Th22 cells in human PDAC and, furthermore, which TILs (tumour-infiltrating lymphocytes) are the main producers of IL-22 is unknown. In the present study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analysed their relationship with the TNM staging system and patient survival. We have demonstrated for the first time that, in PDAC patients, the T-cells co-producing IFN-γ (interferon γ) and exerting perforin-mediated cytotoxicity are the major intra-tumoral source of IL-22. In addition, isolated Th22 cells were able to induce apoptosis, which was antagonized by IL-22. Finally, we observed that the IL-22-producing T-cells were significantly increased in tumour tissue and that this increase was positively correlated with TNM staging of PDAC and poorer patient survival. These novel findings support the dual role of the anti-tumour immune system and that IL-22-producing cells may participate in PDAC pathogenesis. Therefore monitoring Th22 levels could be a good diagnostic parameter, and blocking IL-22 signalling may represent a viable method for anti-PDAC therapies.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Niccolai
authors.affiliation: Immunogenetics and Transplant Biology Service, Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Santena 19, 10126 Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Taddei
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ricci
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Molecular Biology Center and Department of Molecular Biotechnology and Health Sciences, University of Turin, via Nizza 52, 10126 Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rolla
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy Department of Neuro-Skeletal Muscle and Sensory Organs, Interdisciplinary Internal Medicine Unit, Azienda Ospedaliero Universitaria Careggi, 50134 Florence, Italy.
authors.forename: Mario Milco
authors.initials: MM
authors.lastname: D'Elios
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Benagiano
authors.affiliation: Department of Surgery and Translational Medicine, University of Florence, Viale Michelangiolo 41, 50125 Florence, Italy Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bechi
authors.affiliation: Department of Oncology, Division of General and Oncologic Surgery, Azienda Ospedaliera Universitaria Careggi (AOUC), Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Lapo
authors.initials: L
authors.lastname: Bencini
authors.affiliation: Department of Surgery and Translational Medicine, University of Florence, Viale Michelangiolo 41, 50125 Florence, Italy Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Ringressi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Castiglione
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Molecular Biology Center and Department of Molecular Biotechnology and Health Sciences, University of Turin, via Nizza 52, 10126 Turin, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Giordano
authors.affiliation: Centro Oncologico Ematologico Subalpino (COES), AOU Città della Salute e della Scienza di Torino, 10126 Turin, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Satolli
authors.affiliation: Department of Oncology, Division of General and Oncologic Surgery, Azienda Ospedaliera Universitaria Careggi (AOUC), Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Coratti
authors.affiliation: Department of Surgery and Translational Medicine, University of Florence, Viale Michelangiolo 41, 50125 Florence, Italy Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cianchi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy Department of Neuro-Skeletal Muscle and Sensory Organs, Interdisciplinary Internal Medicine Unit, Azienda Ospedaliero Universitaria Careggi, 50134 Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Prisco
authors.affiliation: Immunogenetics and Transplant Biology Service, Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Santena 19, 10126 Turin, Italy Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Molecular Biology Center and Department of Molecular Biotechnology and Health Sciences, University of Turin, via Nizza 52, 10126 Turin, Italy aamedei@unifi.it franco.novelli@unito.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy Department of Neuro-Skeletal Muscle and Sensory Organs, Interdisciplinary Internal Medicine Unit, Azienda Ospedaliero Universitaria Careggi, 50134 Florence, Italy aamedei@unifi.it franco.novelli@unito.it.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019899:Paracrine Communication; D054353:Perforin / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D053804:Granzymes; D007371:Interferon-gamma; D007378:Interleukins; D054353:Perforin; D000097043:Interleukin-22; C573415:IFNG protein, human; C509212:GZMA protein, human
keywords: IFN-γ; IL-22; Th22; pancreatic cancer; tumour-infiltrating lymphocytes