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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Available from: Lucia De Monte, Oct 06, 2015
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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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    ABSTRACT: Cancer immunotherapy through manipulation of the immune system holds great potential for the treatment of human cancers. However, recent trials targeting the negative immune regulators CTLA4, PD-1 and PD-L1 demonstrated that clinically significant antitumor responses were often associated with the induction of autoimmune toxicity. This finding suggests that the same immune mechanisms that elicit autoimmunity may also contribute to the destruction of tumors. Given that the immunological identity of tumors might be largely an immunoprivileged self, autoimmunity may not represent a wholly undesirable outcome in the context of cancer immunotherapy. Rather, targeted killing of cancer cells and autoimmune damage to healthy tissues may be intricately linked through molecular mechanisms, in particular inflammatory cytokine signaling. On the other hand, since chronic inflammation is a well-recognized condition that promotes tumor development, it appears that autoimmunity can be a “double agent” in mediating either pro-tumor or antitumor effects. This review surveys the tumor-promoting and tumoricidal activities of several prominent cytokines: IFN-γ, TNF-α, TGF-β, IL-17, IL-23, IL-4, and IL-13, produced by three major subsets of T helper cells that interact with innate immune cells. Many of these cytokines exert divergent and seemingly contradictory effects on cancer development in different human and animal models, suggesting a high degree of context dependence in their functions. We hypothesize that these inflammatory cytokines could mediate a feedback loop of autoimmunity, antitumor immunity and tumorigenesis. Understanding the diverse and paradoxical roles of cytokines from autoimmune responses in the setting of cancer will advance the long-term goal of improving cancer immunotherapy, while minimizing the hazards of immune-mediated tissue damage and the possibility of de novo tumorigenesis, through proper monitoring and preventive measures.
    Frontiers in Immunology 03/2014; 5:116. DOI:10.3389/fimmu.2014.00116
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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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    ABSTRACT: GATA family of transcription factors are critical for organ development and associated with progression of various cancer types. However, their expression patterns and prognostic values for hepatocellular carcinoma (HCC) are still largely unknown. Expression of GATA transcription factors in HCC cell lines and tissues (n = 240) were evaluated by RT-qPCR, western blot and immunohistochemistry. Cellular proliferation, migration and invasion of HepG2 was evaluated by CCK-8 kit, scratch wound assay and transwell matrigel invasion assay, respectively. GATA2 expression was decreased in HCC cell lines (p = 0.056 for mRNA, p = 0.040 for protein) and tissues (p = 1.27E-25) compared with normal hepatocytes. Decreased expression of intratumoral GATA2 protein significantly correlated with elevated alpha feto-protein (p = 2.7E-05), tumor size >5 cm (p = 0.049), absence of tumor capsule (p = 0.002), poor differentiation (p = 0.005), presence of tumor thrombi (p = 0.005) and advanced TNM stage (p = 0.001) and was associated with increased recurrence rate and decreased overall survival rate by univariate (p = 1.6E-04 for TTR, p = 1.7E-04 for OS) and multivariate analyses (HR = 0.63, 95% CI = 0.43-0.90, p = 0.012 for TTR; HR = 0.67, 95% CI = 0.47-0.95, p = 0.026 for OS). RNAi-mediated knockdown of GATA2 expression significantly enhanced proliferation, migration and invasion of HepG2 cell in vitro. Decreased expression of hematopoietic factor GATA2 was associated with poor prognosis of HCC following resection.
    PLoS ONE 01/2014; 9(1):e87505. DOI:10.1371/journal.pone.0087505 · 3.23 Impact Factor
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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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    ABSTRACT: There has been enormous progress this past decade in the understanding of the biology of dendritic cells (DCs) along with increasing attention for the development of novel dendritic cell (DC)-based cancer therapies. However, the clinical impact of DC-based vaccines remains to be established. This limited success could be explained by suboptimal conditions for generating potent immunostimulatory DCs as well as immune suppression mediated by the tumor microenvironment (TME). Therefore, strategies that optimize the potency of DC vaccines along with newly described therapies that target the TME in order to overcome immune dysfunction may provide durable tumor-specific immunity. These novel interventions hold the most promise for successful cancer immunotherapies.
    Frontiers in Immunology 12/2013; 4:436. DOI:10.3389/fimmu.2013.00436
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