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Background Although allogeneic dendritic cell (DC)-based immunotherapy remains controversial, it offers an alternative and more attractive source than autologous DC vaccines as ‘off-the-shelf’ DCs can be used for multiple patients and could provide additional ‘allogeneic help.’ This study aims to compare efficacy of syngeneic DC vaccines and semi-allogeneic DC vaccines in tumor suppression.Methods Female C57BL/6J mice were inoculated subcutaneously with human papillomavirus E6 and E7-expressing TC-1 cells. Syngeneic bone marrow-derived dendritic cells (BMDCs) were generated from C57BL/6J mice and semi-allogeneic BMDCs with a mutation in either MHC class I or II were generated from B6.C-H2-Kbm1/ByJ or B6(C)-H2-Ab1bm12/KhEgJ mice, respectively. The TC-1 bearing mice received injections of syngeneic or one of the semi-allogeneic H2Db-restricted E7 43-77 peptide-pulsed BMDC vaccines. To investigate the role of different T cell subsets in vaccine-induced tumor control, CD8+ T cells, CD4+ T cells, or Foxp3+ regulatory T cells (Tregs) were depleted at different time points. CD4+ and CD8+ T cells were depleted by antibody administration in C57BL/6J mice, whereas Tregs were selectively depleted by diphtheria toxin in B6.129(Cg)-Foxp3tm3(Hbegf/GFP)Ayr/J transgenic mice. In parallel, in vitro assays were conducted to assess the contribution of CD4+ T cell allogeneic help mediated via mutant MHC class II molecules on DCs, and its impact on CD8+ T cell activation.Results Compared with saline control, the MHC class I semi-allogeneic BMDC vaccine had efficacy similar to the syngeneic BMDC vaccine in suppressing tumor growth. In contrast, the MHC class II semi-allogeneic BMDC vaccine had efficacy significantly superior to the other BMDC vaccines. Both syngeneic and MHC class II semi-allogeneic BMDC vaccines depended on CD4 + T cells, as early CD4+ cell depletion impaired tumor control. Unexpectedly, late CD4+ cell depletion enhanced the efficacy of MHC class II semi-allogeneic BMDCs, due to the depletion of Tregs. In vitro assays showed that antigen-specific CD8+ T cell activation was enhanced by allogeneic CD4+ T cell help via MHC class II semi-allogeneic BMDCs, and this required co-presentation of the peptide-MHC Class I (H2Db) complex and allo-MHC class II on the same DC in vivo.Conclusions MHC class II semi-allogeneic DCs induced superior antitumor responses compared to syngeneic or MHC I semi-allogeneic DC vaccines. This enhanced efficacy involves early activation of allogeneic CD4 + T cells and is boosted by late depletion of Tregs. These findings, supported by in vivo and in vitro analyses, provide mechanistic insights into methods to enhance the therapeutic potential of DC vaccines.Ethics Approval All animal procedures reported in this study that were performed by NCI-CCR affiliated staff were approved by the NCI Animal Care and Use Committee (ACUC) and in accordance with federal regulatory requirements and standards (reference number: METB-033 and MOB-032). All parts of the intramural NIH ACUC program are accredited by AAALAC International.