title: Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer.
abstract: Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1β. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.
authors.affiliation: Tumor Immunology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: De Monte
authors.forename: Michele
authors.initials: M
authors.lastname: Reni
authors.forename: Elena
authors.initials: E
authors.lastname: Tassi
authors.forename: Daniela
authors.initials: D
authors.lastname: Clavenna
authors.forename: Ilenia
authors.initials: I
authors.lastname: Papa
authors.forename: Helios
authors.initials: H
authors.lastname: Recalde
authors.forename: Marco
authors.initials: M
authors.lastname: Braga
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Carlo
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Protti
mesh_terms: D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000503:physiopathology; D018121:Receptors, Cytokine / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: C498762:CRLF2 protein, human; D016207:Cytokines; D053583:Interleukin-1beta; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D000094632:Thymic Stromal Lymphopoietin