Fiche publication
Date publication
août 2018
Journal
Human gene therapy
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier
,
Dr BAGUET Aurélie
,
Pr BORG Christophe
,
Dr FERRAND Christophe
,
Dr GODET Yann
,
Dr DESCHAMPS Marina
,
Dr GALAINE Jeanne
Tous les auteurs :
Mercier-Letondal P, Marton C, Deschamps M, Ferrand C, Vauchy C, Chenut C, Baguet A, Adotévi O, Borg C, Galaine J, Godet Y
Lien Pubmed
Résumé
High risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, enabling HPV-targeted immunotherapy development to treat patients suffering from these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult due to the low frequency of these cell precursors in the peripheral blood, and HPV-positive cancer cells often down-regulate major histocompatibility complex (MHC) class I expression ex vivo limiting the efficacy of MHC class I-restricted approaches. Of particular interest is that the responses can be mediated by both CD4 and CD8 T cells. Given that CD4 T cells play a critical role in coordinating effective anti-tumor responses, the generation of a T helper response in patients suffering from HPV16-associated malignancies would unleash the ultimate potential of immunotherapy. In this view, T cell receptor (TCR) gene transfer could be a relevant strategy to generate HPV16-E7-specific and MHC class II-restricted T cells in sufficient numbers. An HPV16-E7/HLA-DRB1*04 TCR has been isolated from a cancer patient in complete response and retroviral particles encoding this TCR have been produced. The transgenic TCR is highly expressed in transduced T cells, with a functional inducible caspase-9 suicide gene safety cassette. TCR transgenic T cells are HPV16-E770-89-specific and HLA-DRB1*04-restricted, as determined by IFN-γ secretion. CD8 and CD4 T cells are equivalently transduced and secrete IL-2 and IFN-γ when cultured with appropriate targets. We also demonstrate that TCR transgenic T cells recognize the endogenously processed and presented HPV16-E770-89 peptide. In conclusion, our data indicate that the production of MHC class II-restricted HPV16-E7 specific T cells is feasible through TCR gene transfer and could be used for immunotherapy.
Mots clés
CD4 helper T cells, HPV16-E7, MHC class II, TCR gene transfer
Référence
Hum. Gene Ther.. 2018 Aug 23;:
