Cross-Presentation by Dendritic Cells of Tumor Antigen Expressed in Apoptotic Recombinant Canarypox Virus-Infected Dendritic Cells

Motta, Iris; André, Fabrice; Lim, Annick; Tartaglia, James; Cox, William I.; Zitvogel, Laurence; Angevin, Eric; Kourilsky, Philippe

doi:10.4049/jimmunol.167.3.1795

Cited by 64 publications

(51 citation statements)

References 43 publications

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“…It is also known that both immature and mature DC contain immunoproteasomes. Our result of efficient, proteasomedependent, long peptides cross-presentation, as well as other reports of direct presentation [44,45] or cross-presentation of these peptides by DC [46], suggest that the in vitro digest by purified proteasome may not fully reflect a more complex situation in living DC. The presence of both conventional and immunoproteasome in the same cells may result in some type of ''protection'' of certain epitopes (here the MelanA/MART-1 epitope) from immunoproteasome cleavage.…”

Section: Resultssupporting

confidence: 39%

Long‐lasting cross‐presentation of tumor antigen in human DC

et al. 2009

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DC cross-present exogenous antigens on MHC class I molecules, a process required for the onset of anti-tumor immune responses. In order to study the cross-presentation of tumor antigens by human DC, we compared the pathways of cross-presentation of long peptides requiring internalization and intracellular processing with the direct presentation of short peptides, which does not require intracellular processing. We found that, after brief incubations with DC, short peptides were presented to CD8 1 T cells with higher efficiencies than long peptides. After longer times of chase in the absence of peptide, however, the efficiency of presentation of the two types of peptides was reversed. After 2-3 days, DC pulsed with long peptides still activated T cells efficiently, while DC pulsed with short peptides failed to do so. Long-lasting presentation of the long peptides was, at least in part, due to a stored persistent pool of antigen, which was still available for loading on MHC class I molecules after several days of chase. These results show that the use of long synthetic peptides allows the efficient, long-lasting, presentation of tumor antigens, suggesting that long peptides represent an interesting approach for active anti-tumor vaccination.Key words: Cross-presentation . CTL . DC . Long peptides . Melanoma-associated antigen Supporting Information available online IntroductionAdaptative immune responses, especially through CD8 1 T cells, can induce the rejection of solid tumors [1][2][3]. Endogenously expressed tumor-associated antigens (TAA) expressed in tumor cells are recognized by CTL through cognate interactions of the TCR with class I MHC molecules associated with 8-10 amino acid long antigenic peptides. These tumor cell/T-cell interactions, however, are not sufficient to activate naïve T lymphocytes and to induce a memory response. Indeed, professional APC are required for the induction of effector and memory tumor-specific immune responses [4,5]. As most often APC do not endogenously express TAA, uptake and presentation of antigen via an exogenous pathway is required. This so-called ''cross-presentation'' pathway is mainly performed by DC [6,7]. Following the initial observations of cross-priming of T cells by bone-marrowderived cells [8,9], numerous studies investigated the role of cross-priming in the induction of anti-tumor immune responses [10][11][12][13][14] and the strategies to manipulate cross-priming to induce and amplify tumor-specific immune responses [15][16][17][18][19]. Because 380they display a unique capacity to efficiently cross-present exogenous antigens and to prime naïve CD8 1 T cells, DC are good candidates for cancer immunotherapy. The DC-based cancer vaccines that have been tested successfully in mouse models include DC loaded with different forms of tumor antigens, including short peptides, tumor extracts, tumor-derived membrane vesicles and tumor-derived RNA [20][21][22][23]. Nevertheless, these cell-based vaccines present some disadvantages, mainly related to their cost and the...

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Section: Resultssupporting

confidence: 39%

Long‐lasting cross‐presentation of tumor antigen in human DC

et al. 2009

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“…Other viral antigens have also been shown to be cross-presented in vitro including vaccinia virus, canarypox virus, HIV and HCMV, amongst others [78][79][80][81][82][83]. This crosspresentation suggests a mechanism for the antigen transfer between DC subtypes observed in murine models and suggests that the immunoevasive mechanisms of costimulatory molecule downregulation and apoptosis of DC by HSV can be counteracted by uptake by bystander DC.…”

Section: Subsets In Innate and Adaptive Immunity To Hsvmentioning

confidence: 95%

Langerhans cells and viral immunity

2008

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Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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“…Alternatively, the more potent immune responses observed using transduced donor DCs may be a result of more efficient cross-priming by recipient DCs resident in draining lymph nodes or spleen. Several studies now suggest that cross-presentation of Ags delivered by virally infected donor DCs to recipient host lymphoid organ-resident DCs may contribute significantly to the induction of CD8 ϩ T cell responses (20,21,23). Furthermore, very recent studies suggest that cross-presentation favors epitopes derived from stabilized proteins, rather than those from rapidly degraded proteins or short peptides (24 -26).…”

Section: Discussionmentioning

confidence: 99%

Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity

He¹,

Zhang²,

Zhang

et al. 2005

The Journal of Immunology

142

152

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Dendritic cell (DC) therapies are currently being evaluated for the treatment of cancer. The majority of ongoing clinical trials use DCs loaded with defined antigenic peptides or proteins, or tumor-derived products, such as lysates or apoptotic cells, as sources of Ag. Although several theoretical considerations suggest that DCs expressing transgenic protein Ags may be more effective immunogens than protein-loaded cells, methods for efficiently transfecting DCs are only now being developed. In this study we directly compare the immunogenicity of peptide/protein-pulsed DCs with lentiviral vector-transduced DCs, and their comparative efficacy in tumor immunotherapy. Maturing, bone marrow-derived DCs can be efficiently transduced with lentiviral vectors, and transduction does not affect DC maturation, plasticity, or Ag presentation function. Transduced DCs efficiently process and present both MHC class I- and II-restricted epitopes from the expressed transgenic Ag OVA. Compared with peptide- or protein-pulsed DCs, lentiviral vector-transduced DCs elicit stronger and longer-lasting T cell responses in vivo, as measured by both in vivo killing assays and intracellular production of IFN-γ by Ag-specific T cells. In the B16-OVA tumor therapy model, the growth of established tumors was significantly inhibited by a single immunization using lentiviral vector-transduced DCs, resulting in significantly longer survival of immunized animals. These results suggest that compared with Ag-pulsed DCs, vaccination with lentiviral vector-transduced DCs may achieve more potent antitumor immunity. These data support the further development of lentiviral vectors to transduce DCs with genes encoding Ags or immunomodulatory adjuvants to generate and control systemic immune responses.

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Cross-Presentation by Dendritic Cells of Tumor Antigen Expressed in Apoptotic Recombinant Canarypox Virus-Infected Dendritic Cells

Cited by 64 publications

References 43 publications

Long‐lasting cross‐presentation of tumor antigen in human DC

Long‐lasting cross‐presentation of tumor antigen in human DC

Langerhans cells and viral immunity

Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity

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