Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming

Wolfers, Joseph; Lozier, Anne; Raposo, Graça; Régnault, Armelle; Théry, Clotilde; Masurier, Carole; Flament, Caroline; Pouzieux, Stéphanie; Faure, Florence; Tursz, Thomas; Angevin, Eric; Amigorena, Sébastian; Zitvogel, Laurence

doi:10.1038/85438

Cited by 1,391 publications

(1,243 citation statements)

References 35 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: 40%

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: 40%

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

et al. 2009

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Section: Discussionmentioning

confidence: 99%

“…39: 2424 The similarity of such protein to a real tumor antigenic sequence is debatable, but allows demonstration of proof-of-concept [4,47,48]. In the case of EG7 cells, it must be taken into account that OVA is secreted to the cellular milieu [49] and that tumor exosomes may also participate in antigen transfer [50].Our experiments required an immunogenic tumor sensitive to anti-CD137 mAb treatment as monotherapy. Administration of agonistic anti-CD137 mAb induced the eradication of well-established EG7-OVA-derived tumors by a CD8 1 T-cell-dependent mechanism that correlated with an enhanced in vivo CTL activity against the immunodominant tumor antigen.…”

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confidence: 99%

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

et al. 2009

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Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves costimulation of tumor-specific CD8 1 T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8b 1 T-celldependent mechanism that correlates with increased CTL activity. Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen crosspresentation revealed that CD11c 1 cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumordraining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent protein-C57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA [257][258][259][260][261][262][263][264] epitope and in the antitumor efficacy induced by anti-CD137 mAb.Key words: CD137 (4-1BB) . Cross-priming . CTL . DC . Tumor immunity Supporting Information available online Introduction CD137, also known as 4-1BB, is a TNF-receptor family costimulatory molecule originally identified on activated T cells [1]. Its natural ligand CD137L is found on APC, including B cells, macrophages, and DC [2]. In the presence of TCR engagement, signaling through CD137 leads to increased T-cell proliferation, cytokine production, and prolonged CD8 1 T-cell survival in vitro [2]. Administration of agonistic anti-CD137 mAb either alone or following peptide vaccination is capable of inducing the eradication of established tumors in several transplantable tumor models [3,4]. This anti-tumor effect is dependent on CD8 1 T cells that show increases in tumor-specific cytotoxic activity and associated IFN-g production [3,4]. Recent studies have demonstrated that the activity of anti-CD137 mAb treatment is also dependent on their ability to enhance the survival of CD8 1 CTL, and on the prevention/reversal of established anergy [5][6][7]. In addition, antigen-independent anti-CD137 mAb effects have been described for memory T cells, and CD137 seems to be an Ã These authors contributed equally to this work.ÃÃ These authors share equal senior authorship. 2424important player in the differentiation of memory cells [8][9][10]. CD137 can also be expressed by activated NK cells [11], myeloid leukocytes [12] including DC [13,14], and tumor endothelial cells [15]. However, the role of CD137 molecules expressed on these non-T cells during tumor immunotherapy remains undefined [13,16].As naïve CTL do not express CD137 on their surface, susceptibility to CD137 triggering depends on prior up-regulation of this receptor [5]. This requires antigen rec...

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“…To improve vaccine potency, tumour-specific antigens expressed on the surface of a tumour cell-derived exosome can be used to induce DC priming and T cell activation, leading to anti-tumour immunity [109,110]. For example, the addition of exosome membrane-bound HSP70 has been suggested as a method to maximize the vaccination effect of tumour cell-derived exosomes and induce a stronger immune response [111].…”

Section: Therapeutic Applications Of Surface-modified Evsmentioning

confidence: 99%

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

Yang

Hong

Cho

et al. 2018

J of Extracellular Vesicle

186

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Membrane proteins are of great research interest, particularly because they are rich in targets for therapeutic application. The suitability of various membrane proteins as targets for therapeutic formulations, such as drugs or antibodies, has been studied in preclinical and clinical studies. For therapeutic application, however, a protein must be expressed and purified in as close to its native conformation as possible. This has proven difficult for membrane proteins, as their native conformation requires the association with an appropriate cellular membrane. One solution to this problem is to use extracellular vesicles as a display platform. Exosomes and microvesicles are membranous extracellular vesicles that are released from most cells. Their membranes may provide a favourable microenvironment for membrane proteins to take on their proper conformation, activity, and membrane distribution; moreover, membrane proteins can cluster into microdomains on the surface of extracellular vesicles following their biogenesis. In this review, we survey the state-of-the-art of extracellular vesicle (exosome and small-sized microvesicle)-based therapeutics, evaluate the current biological understanding of these formulations, and forecast the technical advances that will be needed to continue driving the development of membrane protein therapeutics.

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Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming

Cited by 1,391 publications

References 35 publications

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

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

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

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