pDCs efficiently process synthetic long peptides to induce functional virus‐ and tumour‐specific T‐cell responses

Abstract

Keywords: Cancer r Cross-presentation r Long peptides r Plasmacytoid dendritic cells r Viral infectionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDeveloping efficient therapeutic strategies for cancer and viral infection remains challenging. Successful immunotherapies should elicit robust cell-mediated immunity that is able to eliminate tumour-or virus-infected cells, since strong and multi-specific cytotoxic T lymphocytes (CTLs) responses are often associated with better clinical outcomes in cancer [1] and chronic infectious diseases [2,3]. In the past, the main focus of immunotherapies was on eliciting cytotoxic CD8 + T-cell responses; however, accumulatCorrespondence: Dr. Caroline Aspord e-mail: carolineaspord@yahoo.com ing evidence suggests that CD4 + T cells also play an important role in sustaining immune responses against cancer and infection [4,5]. CD4 + T cells provide critical help to CD8 + T cells, promoting their survival, expansion, and acquisition of effector functions [6,7]. CD4 + T cells also display direct antitumour cytolytic activity [8]. In melanoma, more favourable clinical outcomes are associated with immune responses towards many MHC class I and class II epitopes derived from several tumour antigens [9][10][11]. T-cell immunity, particularly when both CD4 + and CD8 + arms of immunity are involved, has also been shown to protect against cytomegalovirus (CMV) reactivation and disease [12]. Therefore, both CD4 + and CD8 + T cells play a pivotal role in inducing and maintaining therapeutic anti-tumour and anti-viral immunity.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2880-2892 Antigen processing As their size prevents a direct binding to MHC class I molecules, SLPs must be taken up and processed before they can be presented to T cells. Such cross-presentation involves dendritic cells (DCs) [21,22], which go on to cross-prime CTL and Th-cell immune responses [23]. Myeloid DCs (mDCs) have already been shown to cross-present SLPs and subsequently induce immune responses [22,24]. Plasmacytoid DCs (pDCs) are another interesting DC subset, also playing a critical role in shaping and regulating immune responses [25,26]. pDCs appear as novel vectors for immunotherapy for both cancer and infections [27][28][29][30], but their ability to cross-present SLP has never been investigated. Nonetheless, there is increasing evidence that pDCs effectively capture, process, and present antigens to T cells [31] Fig. 1C and D). Interestingly, despite some variations depending on the donors used, cross-presentation of long peptides significantly improved with a longer processing time (24 h) with both the pDC line ( Fig. 1E) and primary pDCs (Fig. 1F). To exclude any bystander effects of the peptivator pools, we used three individual long peptides encompassing the cross-presented epitope. All of them were well processed and cross-presented by pDCs (Fig. 2). The pDC line induced a sligh...

Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer

“…Recent studies in mice have shown that pDCs can effectively induce anti-tumor CD8+ T-cell responses [ 30 ], and that pDCs efficiently cross-present TAA to trigger T-cell responses [ 28 ]. In the present study, we asked if there was any correlation between survival, patients’ in vitro T-cell responses to Her-2 peptides, and frequencies of circulating DCs.…”

“…An effective way to induce both TAA-reactive CD4+ and CD8+ T-cell responses is by using synthetic long peptides (SLPs) [ 25 , 26 ]. Antigen presentation by pDCs could contribute to the induction of specific CD4+ and CD8+ T-cell responses [ 27 , 28 ], but this would be contrary to the findings discussed above implying that high levels of pDCs in the tumor and low levels in the blood have a negative prognostic impact. Thus, the present study focuses on investigating the prognostic relevance of circulating antigen-presenting cells including total DCs, mDCs and pDCs separately, together with functional Her-2-reactive T-cells assayed in vitro, and an assessment of the impact of immunosuppressive cells on 5-year survival of breast cancer patients.…”

Exosome-driven transfer of tumor-associated Pioneer Translation Products (TA-PTPs) for the MHC class I cross-presentation pathway

“… 42 Most cross-presentation studies have been carried out using full-length proteins as the source of peptides but a few recent studies report that SLP can be cross-presented in mice by different types of DCs from BMDCs to pDCs. 10,12 It is possible that the uptake and processing of antigenic peptide substrates by the pAPCs for cross-presentation is specialized toward a certain type, and context, of peptide material and it will be interesting to compare if cross-presentation by different types of pAPCs depends on the nature of the antigen. In view of this, it is interesting that we detect PTP products in the exosomes of tumor-derived cell lines and that PTP-loaded exosomes alone are sufficient to trigger an efficient cross-presentation by BMDCs.…”

“… 8,9 Synthetic long peptides (SLP) of 22 to 24 amino acids of the Ovalbumin or HIV-1 Gag proteins are a better source of peptides for the cross-presentation pathway as compared to full-length proteins. 10-12 Together with the fact that antigenic peptides derived from non-canonical mRNA translation such as intron or alternative open reading frames have been detected on MHC class I molecules highlights the need to investigate the role of alternative sources of peptides for CD8 + T cell activation against tumor cells. 13-15 Recent studies have shown that alternative translation products such as DRiPs (defective ribosomal products) 16 or pioneer translation products (PTPs) constitute an important source of peptides for the endogenous class I pathway.…”

The Known Unknowns of the Human Dendritic Cell Network

“…Blood and lymphoid organ pDCs cross-present efficiently soluble ( 41 , 44 , 67 , 70 , 71 ), viral ( 71 – 74 ), cell-associated antigen ( 67 , 75 ), or antigen targeted to surface receptors such as CD40, DCIR, CD205, BDCA2/CD303, or CD32 ( 67 , 69 , 76 ).…”