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 . © 2018 UICC