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T-cell immunity induced and reshaped by an anti-HPV immuno-oncotherapeutic lentiviral vector
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Edité par CCSD ; Nature Research -
International audience. Werecently developed animmuno-oncotherapy against human papillomavirus (HPV)-induced tumorsbased on a lentiviral vector encoding the Early E6 and E7 oncoproteins of HPV16 and HPV18genotypes, namely “Lenti-HPV-07”. The robust and long-lasting anti-tumor efficacy of Lenti-HPV-07is dependent on CD8+ T-cell induction and remodeling of the tumor microenvironment. Here, we firstestablished that anti-vector immunity induced by Lenti-HPV-07 prime has no impact on the efficacy ofahomologous boost to amplify anti-HPV T-cell immunity. To longitudinally monitor the evolution of theT-cell repertoire generated after the prime, homologous or heterologous boost with Lenti-HPV-07, wetracked T-cell clonotypes by deep sequencing of T-Cell Receptor (TCR) variable β and α chainmRNA,applied to whole peripheral blood cells (PBL) and a T cell population specific of an immunodominantE7HPV16 epitope. We observed a hyper-expansion of clonotypes post prime, accompanied byincreased frequencies of HPV-07-specific T cells. Additionally, there was a notable diversification ofclonotypes post boost in whole PBL, but not in the E7HPV16-specific T cells. We then demonstratedthat the effector functions of such Lenti-HPV-07-induced T cells synergize with anti-checkpointinhibitory treatments by systemic administration of anti-TIM3 or anti-NKG2A monoclonal antibodies.While Lenti-HPV-07 is about to enter a Phase I/IIa clinical trial, these results will help better elucidate itsmode of action in immunotherapy against established HPV-mediated malignancies.
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