Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer

Departments of Medical Oncology, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France.
Cancer Research (Impact Factor: 9.33). 06/2011; 71(16):5423-34. DOI: 10.1158/0008-5472.CAN-11-0367
Source: PubMed


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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Available from: Vanja Sisirak, Jul 22, 2015
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    • "Immune cells also play a major role in the immune escape in EOC [58]. The EOC-specific recruitment of CD4+CD25+FoxP3+ regulatory T-cells (Treg), tolerogenic dendritic cells (DC), B7-H4+ tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) fosters immune privilege and predicts reduced survival in EOC (Table 1) [23,36,44,59-62]. Accumulation of Treg is now well documented in various tumors including EOC [23,36,38-41]. "
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    • "Actually, we have already shown an altered expression of CD86 in Mo-DCs from advanced cancer patients, which was, apparently, corrected by an immunotherapeutic approach [49]. Importantly, the presence of pDCs in tumor sites has been also related to poor prognosis in cancer patients [30], and their functional investigation revealed a considerable low to absent IFN-alpha production in breast and ovarian cancer [50] [51]. The tumor-associated stroma and cancer cells per se can generate signals that drive DC to a tolerogenic pathway, characterized, mainly, by a poor upregulation of MHC class II and costimulatory molecules and absent or low production of proinflammatory cytokines [52], thus favoring tumor "
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    ABSTRACT: Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer.
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    • "On the other hand, pDCs have the capacity to induce tolerance by establishing regulatory T cells (Matta et al., 2010). pDC infiltration into murine and human tumors and tumordraining lymph nodes often correlates with poor prognosis (Gerlini et al., 2007; Jensen et al., 2011; Labidi-Galy et al., 2011). This is explained by dysfunctionality of tumor-associated pDCs, i.e. lack of type I interferon production or activation of cytotoxic lymphocytes (CTLs). "
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