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Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy
Author(s) -
Beziaud Laurent,
Boullerot Laura,
Tran Thi,
Mansi Laura,
MarieJoseph Elodie Lauret,
Ravel Patrice,
Johannes Ludger,
Bayry Jagadeesh,
Tartour Eric,
Adotévi Olivier
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31842
Subject(s) - temsirolimus , cytotoxic t cell , cd8 , cancer research , immunology , medicine , antigen , pharmacology , biology , pi3k/akt/mtor pathway , in vitro , signal transduction , biochemistry , discovery and development of mtor inhibitors
mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor‐specific CD8 T‐cell responses induced by vaccination. Furthermore, tumor‐specific CD8 T cells induced by the bi‐therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127 + CD62L + ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (T regs ) expansion in vivo limits the efficacy of the bi‐therapy by altering the antitumor CD8 T‐cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent T regs induction considerably improved the efficacy of the bi‐therapy by enhancing CD8 T cells‐mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit T regs .