T-cell immunity induced and reshaped by an anti-HPV immuno-oncotherapeutic lentiviral vector
Résumé
Werecently developed animmuno-oncotherapy against human papillomavirus (HPV)-induced tumors
based on a lentiviral vector encoding the Early E6 and E7 oncoproteins of HPV16 and HPV18
genotypes, namely “Lenti-HPV-07”. The robust and long-lasting anti-tumor efficacy of Lenti-HPV-07
is dependent on CD8+ T-cell induction and remodeling of the tumor microenvironment. Here, we first
established that anti-vector immunity induced by Lenti-HPV-07 prime has no impact on the efficacy of
ahomologous boost to amplify anti-HPV T-cell immunity. To longitudinally monitor the evolution of the
T-cell repertoire generated after the prime, homologous or heterologous boost with Lenti-HPV-07, we
tracked 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 immunodominant
E7HPV16 epitope. We observed a hyper-expansion of clonotypes post prime, accompanied by
increased frequencies of HPV-07-specific T cells. Additionally, there was a notable diversification of
clonotypes post boost in whole PBL, but not in the E7HPV16-specific T cells. We then demonstrated
that the effector functions of such Lenti-HPV-07-induced T cells synergize with anti-checkpoint
inhibitory 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 its
mode of action in immunotherapy against established HPV-mediated malignancies.
Domaines
Sciences du Vivant [q-bio]Origine | Publication financée par une institution |
---|---|
Licence |