Abstract 472: In vivo activation of plasmacytoid dendritic cells using TLR7-L induced an efficient antitumoral effect in a murine mammary preclinical tumor model

Abstract

Abstract Dendritic cells (DC) are professional antigen presenting cells involved in both the induction and the polarization of adaptive immune response. Among them figure conventional myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC), the last ones being involved in the induction of antiviral immune response through type I interferons production. In human breast cancer, we have previously shown that pDC infiltration is an independent factor correlated with a poor prognosis. Although pDC can induce efficient T cell responses against viral or endogenous antigens, it remains unclear whether pDC are efficient for cross presentation of tumor antigens acquired from dying tumor cells. Moreover, pDC have been described in some contexts to be involved in the induction of immune tolerance by promoting regulatory T cell (Treg) differentiation. Thus herein we evaluate their ability to induce efficient antitumoral response after activation by viral signals such as TLR7L or TLR9L. First, we developed several preclinical murine mammary tumor models derived from spontaneous mammary tumors arose in transgenic mice MMTV-Her2/neu expressing the rat proto-oncogene neu under the control of MMTV promoter. Several tumor cell lines (NEU) expressing HER2/Neu were derived from these spontaneous mammary tumors and were implanted in the 4th fad pad of immunotolerant transgenic mice MMTV-Her2/neu or in immunocompetent FVB wild type mice witch developed an antibody immune response against the rat Her2/neu proto-oncogene. All NEU cell lines were highly tumorigeneic in immunotolerant mice but interestingly when implanted in FVBwt mice some were rejected, some escape by immunoediting with a selection of a NEU negative variant and one (NEU15) escape by another mechanism showing as in human breast cancer the maintenance of Her2/Neu expression despite an anti-tumoral immune response. We showed that NEU15 tumors in FVBwt mice (NEU15wt) were significantly more infiltrated by pDC and Treg than NEU15 tumors in immunotolerant transgenic mice (NEU15Tg). Secondly, we focused on this NEU15wt preclinical model and analyzed the functional status of tumor associated pDC (TApDC) and TAmDC. We showed that TApDC are altered for their capacity to secrete type I IFN in response to TLR9 engagement while preserving their ability to respond to viral signals such as Influenza and TLR7 ligands. TAmDC undergo a spontaneous maturation in culture independently of TLR engagement and secrete inflammatory cytokines (TNFα, RANTES) but also IL-10 and no IL12. In vivo immuno intervention using intra-tumoral injection of TLR-7L (50μg D13 and D20) in pre-established NEU15wt tumors allowed 50% of complete tumor rejection. IFNα production was detected in mice sera 3 hours after TLR-7L intratumoral injection. The impact of in vivo depletion of pDC on the therapeutic efficiency of TLR7L is under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 472. doi:10.1158/1538-7445.AM2011-472