De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C, Protti MPIntratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 208: 469-478

Tumor Immunology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
Journal of Experimental Medicine (Impact Factor: 12.52). 02/2011; 208(3):469-78. DOI: 10.1084/jem.20101876
Source: PubMed


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.

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    • "A study of pancreatic cancer patients demonstrated that tumor-produced cytokines (TNF and IL-1β) triggered activation of a Th2 phenotype in cancer-associated fibroblasts, dendritic cells, and naïve CD4+ T cells. Moreover, the ratio of Th2:Th1 CD4+ T lymphocytes present at the tumor site was negatively correlated with patient survival (52). In a humanized mouse model implanted with human breast carcinoma, Th2 cytokine expression was detected in both cancer cells and tumor-promoting CD4+ T cells within the tumor microenvironment. "
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    • "GATA1 and GATA2 are mainly thought as hematopoietic factors and intensely studied in hematopoietic malignancies [5]–[7]. GATA3 has been widely accepted as a classical modulator of T helper type 2 (Th2) immune response [8], which is reported to promote progression of breast [9] and pancreatic cancers [10]. Meanwhile, GATA3 has been demonstrated as a tumor suppressor gene of breast tumor [11]. "
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    • "Thymic Stromal Lymphopoietin has also been described to modulate DC function and drive TH2 responses (32). TSLP produced by tumor cells has been shown to induce detrimental TH2 cells responsible for increasing tumor growth in breast cancer and pancreatic cancer through the secretion of IL-13 and IL-4 (33, 34). "
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