Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer
Open Access
- 21 February 2011
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 208 (3), 469-478
- https://doi.org/10.1084/jem.20101876
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.Keywords
This publication has 45 references indexed in Scilit:
- Pancreatic CancerNew England Journal of Medicine, 2010
- Immunity, Inflammation, and CancerCell, 2010
- Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent MannerCancer Cell, 2010
- TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasisThe Journal of Experimental Medicine, 2009
- Simple: A Sequential Immunoperoxidase Labeling and Erasing MethodJournal of Histochemistry & Cytochemistry, 2009
- Cancer-related inflammationNature, 2008
- Microenvironmental regulation of metastasisNature Reviews Cancer, 2008
- Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκBProceedings of the National Academy of Sciences, 2007
- The Three Es of Cancer ImmunoeditingAnnual Review of Immunology, 2004
- Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLPNature Immunology, 2002