Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer.
ABSTRACT In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4(+)CD123(+)BDCA2(+) pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4(+) T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance.
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ABSTRACT: Immunosuppressive lymphocytes, such as regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs), play crucial roles in tumor escape. To investigate the roles of Tregs and pDCs in papillary thyroid cancer (PTC) plus multinodular non-toxic goiter (MNG), thyroid tissue and blood samples from 30 patients with PTC plus MNG and 30 MNG alone were analyzed for CD4(+) T cell, CD8(+) T cell, FoxP3(+) Treg, ICOS(+)FoxP3(+) Treg, and pDC numbers by immunohistochemistry (IHC), immunofluorescence, and flow cytometry. Plasma concentration of the cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β) were measured by enzyme-linked immunosorbent assay as well. Both in thyroid tissue and peripheral blood, the numbers of Foxp3(+) Treg were significantly higher in patients with PTC plus MNG compared to patients with MNG alone; and as a prognostic marker, ICOS(+)Foxp3(+) Tregs represent a stronger predictor of disease progression than the total numbers of Foxp3(+) Tregs. Furthermore, a positive correlation between pDC and ICOS(+)Foxp3(+) Treg numbers in tissue of patients with PTC plus MNG was observed, suggesting that PTC-derived pDCs may induce the differentiation of naive CD4(+) T cells into ICOS(+)Foxp3(+)Tregs. This may be one of the mechanisms underlying tumor escape in PTC plus MNG patients. Our results suggest that Tregs and pDCs together contribute to the tumor escape in patients with PTC plus MNG.Endocrine 12/2012; · 1.42 Impact Factor
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ABSTRACT: Pattern recognition receptors (PRRs) are known for many years for their role in the recognition of microbial products and the subsequent activation of the immune system. The 2011 Nobel Prize for medicine indeed rewarded J. Hoffmann/B. Beutler and R. Steinman for their revolutionary findings concerning the activation of the immune system, thus stressing the significance of understanding the mechanisms of activation of the innate immunity. Such immunostimulatory activities are of major interest in the context of cancer to induce long-term antitumoral responses. Ligands for the toll-like receptors (TLRs), a well-known family of PRR, have been shown to have antitumoral activities in several cancers. Those ligands are now undergoing extensive clinical investigations both as immunostimulant molecules and as adjuvant along with vaccines. However, when considering the use of these ligands in tumor therapy, one shall consider the potential effect on the tumor cells themselves as well as on the entire organism. Recent data indeed demonstrate that TLR activation in tumor cells could trigger both pro- or antitumoral effect depending on the context. This review discusses this balance between the intrinsic activation of PRR in tumor cells and the extrinsic microenvironment activation in term of overall effect of PRR ligands on tumor development. We review recent advances in the field and underline appealing prospects for clinical development of PRR agonists in the light of our current knowledge on their expression and activation.Targeted Oncology 03/2012; 7(1):29-54. · 3.46 Impact Factor
Article: Targeting regulatory T cells.[Show abstract] [Hide abstract]
ABSTRACT: Cancers express tumor-associated antigens that should elicit immune response to antagonize the tumor growth, but spontaneous immune rejection of established cancer is rare, suggesting an immunosuppressive environment hindering host antitumor immunity. Among the specific and active tumor-mediated mechanisms, CD4(+)CD25(high) T regulatory cells (Treg) are important mediators of active immune evasion in cancer. In this review, we will discuss Treg subpopulations and the mechanisms of their suppressive functions. Treg depletion improves endogenous antitumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy. We will also discuss specific strategies for devising effective cancer immunotherapy targeting Treg.Targeted Oncology 02/2012; 7(1):15-28. · 3.46 Impact Factor