Abstract 1910: Infiltration of ovarian carcinoma by altered plasmacytoid dendritic cells could contribute to local immune tolerance

Abstract

Abstract Ovarian carcinomas are usually considered as immunogenic tumors, as they are capable of inducing tumor-associated antigen immunity. However, immune system fails to eradicate established tumors partly due to alteration of immunosurveillance and induction of an active process of « tolerization » by the tumor microenvironment. We prospectively collected blood, tumors, and ascites samples from 38 patients with ovarian carcinomas (localized and advanced stages) and 35 healthy donors that gave written informed consent. Lin−CD4+CD11c−CD123+BDCA2+ pDC are the most abundant DC subset within ovarian carcinomas and neoplasic ascitis while they are profoundly depleted in peripheral blood of ovarian carcinoma patients compared to healthy donors. The depletion of pDC in patient's blood is partially restored when they are in complete remission (after chemotherapy and surgery). These observations suggest preferential pDC recruitment into tumor tissues that may involve CCR7 and CD62L which are downregulated in Tumor-associated (TA)-pDC compared to ascitis or blood pDC. Furthermore, TApDC express a partially mature phenotype compared to patient's blood and ascitis pDC that may reflect an in situ activation. Importantly, ex vivo TApDC produce lower amounts of IFN-α, TNF-α, IL-6 and RANTES in response to TLR ligands than ascitis or healthy donor pDC, suggesting a specific inhibition by ovarian tumor environment. In vitro, tumor or ascitis-derived surnageants (SNTUM) induce inhibition of the production of IFN-α and TNF-α by healthy pDC in response to TLR activation, suggesting the implication of soluble factors in this functional inhibition. In addition, TApDC but not ascitis pDC or healthy donors pDC direct allogeneic naive CD4+ T lymphocytes to produce high amounts of IL-10. Thus, TApDC may contribute to the tumor environmental immunosuppressive network. Elucidation of the mechanisms of dysfunctions of TApDC could have clinically relevant implications for future therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1910.