The Shiga toxin B‐subunit targets antigen in vivo to dendritic cells and elicits anti‐tumor immunity

Abstract

The non-toxic B-subunit of Shiga toxin (STxB) interacts with the glycolipid Gb 3 , which is preferentially expressed on dendritic cells (DC) and B cells. After administration of STxB chemically coupled to OVA (STxB-OVA) in mice, we showed that the immunodominant OVA 257-264 peptide restricted by K b molecules is specifically presented by CD11c + CD8a -DC, some of them displaying a mature phenotype. Using mice carrying a transgene encoding a diphtheria toxin receptor (DTR) under the control of the murine CD11c promoter, which allows inducible ablation of DC, we showed that DC are required for efficient priming of CTL after STxB-OVA vaccination. Immunization of mice with STxB-OVA induced OVA-specific CD8 + T cells detected ex vivo; these cells were long lasting, since they could be detected even 91 days after the last immunization and were composed of both central and memory T cells. Vaccination of mice with STxB-OVA and STxB coupled to E7, a protein derived from HPV16, inhibited tumor growth in prophylactic and therapeutic experiments. This effect was mainly mediated by CD8 + T cells. STxB therefore appears to be a powerful carrier directly targeting DC in vivo, resulting in a strong and durable CTL response associated with tumor protection.

Immunothérapie des cancers

“…Cette corrélation est aujourd'hui discutée car elle pourrait dépendre plus de la durée du traitement que de la réponse clinique [34]. En revanche, les manifestations auto-immunes observées après administration de l'anticorps anti-CTLA-4 sont plus précoces et restent corrélées à la réponse au traitement [35,57] [39][40][41][42]. Ces nouveaux outils associés à l'identification de nouveaux adjuvants pour augmenter l'immunité cellulaire devraient permettre de mieux amplifier la réponse immune antitumorale sur les plans qualitatif et quantitatif.…”

L’apport des nouvelles technologies en vaccinologie

“…Un vaccin thérapeutique contre le cancer du col de l'utérus, fondé sur ce vecteur, est en cours de développement clinique par BT Pharma [28]. D'autres toxines bactériennes, comme la sous-unité B de la toxine de Shiga [29] ou l'antigène protecteur (PA) produit par Bacillus anthracis [30] sont également employés comme vecteurs d'antigènes. Des protéines de choc thermique, comme Hsp70 ou gp96, sont capables de se lier à divers récepteurs à la surface des CD, notamment au CD91 [31], et ont été employées dans plusieurs modèles expéri-mentaux pour vectoriser des antigènes [32].…”

Correlation between Shiga toxin B‐subunit stability and antigen crosspresentation: A mutational analysis

“…STxB has been used as a tool for the characterization of the retrograde route [13,14], and in biomedical research as a delivery tool for immunotherapy [3,15] and cancer targeting [16,17]. It was shown that STxB delivers exogenous peptides into the MHC class I and II pathways of human and mouse dendritic cells (DCs) and induces humoral and cell-mediated immune responses that protect mice from tumor growth [18][19][20][21][22]. Functional TAP and proteasome activities are required for STxB-induced MHC class I-restricted antigen presentation, strongly suggesting that STxB delivers exogenous antigenic proteins and peptides across membranes into the cytosolic compartment [19].…”