Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer

Gracht, E.T.I. van der; Schoonderwoerd, M.J.; Duikeren, S. van; Yilmaz, A.N.; Behr, F.M.; Colston, J.M.; Lee, L.N.; Yagita, H.; Gisbergen, K.P.J.M. van; Hawinkels, L.J.A.C.; Koning, F.; Klenerman, P.; Arens, R.

doi:doi:10.1136/jitc-2020-001133

Background Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8(+) T cells elicited upon immunization with adenoviral vectors. Methods Adenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (10(7), 10(8) or 10(9) infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated. Results The adenoviral vaccines elicited inflationary E7-specific memory CD8(+) T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8(+) T cells in the circulation related to the development of E7...Show moreBackground Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8(+) T cells elicited upon immunization with adenoviral vectors. Methods Adenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (10(7), 10(8) or 10(9) infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated. Results The adenoviral vaccines elicited inflationary E7-specific memory CD8(+) T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8(+) T cells in the circulation related to the development of E7-specific CD8(+) tissue-resident memory T (T-RM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8(+) T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8(+) T-RM cells. Moreover, the formation of CD8(+) T-RM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization. Conclusions Together, these data show that adenoviral vector-induced CD8(+) T cell inflation promotes protective T-RM cell populations, and this can be enhanced by targeting CTLA-4.Show less

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Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer