Aline Le Moignic

Despite current therapy, head and neck squamous cell carcinomas (HNSCCs) arising from various mucosal sites of the upper aero-digestive tract frequently relapse in a loco-regional manner and have a poor prognosis. Our objective was to validate an innovative mucosal route of vaccination using plasmo virus-like particles (pVLPs) in a pre-clinical orthotopic model of HNSCCs. For this purpose, we used pVLP-E7, that are plasmid DNA encoding retroviral virus-like particles carrying a truncated E7 oncoprotein from HPV-16 as antigen model, to vaccinate mice bearing pre-established TC-1 tumors implanted into the buccal mucosa. pVLP-E7 were combined with clinical grade TLR agonists (Imiquimod and CpG-ODN). In this pre-clinical orthotopic model, whose tumor microenvironment resembles to those of human HNSCCs, different mucosal vaccination routes were tested for their ability to elicit efficient immune and antitumoral responses. Results showed that mucosal intra-cheek (IC) vaccinations using pVLP-E7, comparatively to intradermic vaccinations (ID), gave rise to higher mobilization of mucosal (CD49a+) CD8+ specific effector T cells in both tumor draining lymph nodes (TdLNs) and tumor microenvironment resulting in better antitumor effects and in a long-term protection against tumor rechallenge. In vivo CD8+ depletion demonstrated that antitumoral effects were fully dependent upon the presence of CD8+ T cells. Validation of IC mucosal vaccinations with pVLPs combined with adjuvants using a pre-clinical orthotopic model of HNSCC provides valuable pre-clinical data to rapidly envision the use of such therapeutic vaccines in patients with HNSCCs, inasmuch as vaccinal components and adjuvants can be easily obtained as clinical grade reagents.

Introduction Oral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis. Materials and Methods Cells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay. Results Normal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p<0.05 for blood), of monocytes-macrophages (p<0.01 for blood) and of CD4 + T cells expressing CD45RO and CCR6 (p<0.001 for blood; p<0.0001 for TME) as well as higher levels of IL-6 (p<0.01 for sera, p<0.05 for tumor supernatant) were observed in SD patients as compared to NSND OSCC patients and HD. High percentages of CD4 + T cells expressing CD45RO and CCR6 cells in tumor tissue (p=0.05) and blood (p=0.05) of SD OSCC patients were also associated with a poorer prognosis while a high percentage of regulatory T cells (Treg) in tumor tissue was associated with a more favorable prognostic factor (p=0.05). Also, a higher percentage of blood CD8 + T lymphocytes among CD45 + cells in NSND patients was associated with a better disease-free survival (p=0.004). Conclusion Granulocytes, monocytes-macrophages, and CD4 + T cells expressing CD45RO and CCR6 in blood and TME as well as serum IL-6 can therefore distinguish OSCC SD and NSND patients. Quantifying the proportion of CD4 + T cells expressing CD45RO and CCR6 and of Treg in SD patients and CD8 + T cells in NSND patients could help defining the prognostic of OSCC patients.

Les cellules immunitaires engendrent des réponses anti-tumorales en reconnaissant les antigènes spécifiques des tumeurs. Un échec du contrôle immunitaire est le plus souvent observé. Ceci est à l’origine de travaux de recherche dont l’objectif est de concevoir l’immunothérapie des cancers. Le meilleur exemple est le développement des anticorps monoclonaux (thérapie ciblée), qui sont une avancée majeure dans le traitement des cancers. Le traitement des cancers des VADS (Voies Aéro-Digestives Supérieures) reste conventionnel, utilisant chirurgie, radiothérapie et chimiothérapie classique. L’objectif de ce travail est une mise au point sur les espoirs de l’immunothérapie dans le traitement des cancers des VADS.

Les cancers des voies aéro-digestives supérieures (VADS) sont un problème de santé publique majeur. Chez l’homme, ces cancers arrivent en troisième place en termes de fréquence en France. Le pronostic est sombre, la survie des patients ne dépasse pas 20 % à 10 ans. Il est nécessaire de s’intéresser à l’environnement tumoral, afin de mieux comprendre les étapes de formation et d’extension, ainsi que les interactions avec le système immunitaire de l’hôte. L’identification de nouveaux biomarqueurs, témoins du processus cancéreux mais aussi d’une éventuelle réponse immunitaire anti-tumorale pourraient constituer des éléments du diagnostic et du pronostic, mais aussi des cibles thérapeutiques. Cette revue de la littérature a pour but de faire le point sur la réponse immunitaire et l’échappement tumoral des cancers des VADS.