Enhancing DC cancer vaccine by allogeneic MHC class II expression and Treg depletion
Noriko Seishima, William Becker, Purevdorj B. Olkhanud, Hoyoung M. Maeng, Miguel A. Lopez-Lago, William V. Williams, Jay A. Berzofsky
Noriko Seishima, William Becker, Purevdorj B. Olkhanud, Hoyoung M. Maeng, Miguel A. Lopez-Lago, William V. Williams, Jay A. Berzofsky
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Research Article Immunology Oncology

Enhancing DC cancer vaccine by allogeneic MHC class II expression and Treg depletion

Abstract

We assessed the therapeutic efficacy of a semiallogeneic dendritic cell (DC) vaccine in comparison to a syngeneic one for suppression of B16-F10 and TC-1 tumors. Syngeneic bone marrow–derived DCs (BMDCs) were generated from C57BL/6J mice and semiallogeneic 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. We demonstrated in vivo and in vitro that the MHC class II semiallogeneic BMDC vaccine had superior efficacy over the syngeneic and the MHC class I semiallogeneic BMDC vaccine, providing allogeneic CD4+ T cell help to enhance the antitumor CD8+ T cell response through allogeneic stimulation by the mutant MHC class II molecules. We discovered that this help was induced only at an early stage of tumor growth and at a later stage of tumor growth; combining our BMDC vaccine with Treg depletion enhanced tumor suppression. We demonstrated the improved efficacy of a semiallogeneic BMDC vaccine that kept tumor-peptide presentation intact on syngeneic MHC class I molecules so that mutant MHC class II could provide allogeneic help. This strategy should enable promising new DC-based cancer immunotherapies, offering an alternative to autologous DC vaccines by incorporating allogenicity as an adjuvant.

Authors

Noriko Seishima, William Becker, Purevdorj B. Olkhanud, Hoyoung M. Maeng, Miguel A. Lopez-Lago, William V. Williams, Jay A. Berzofsky

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Figure 2

The E743–77 peptide–pulsed MHC class II semiallogeneic mature BMDC vaccine is superior in delaying TC-1 tumor growth, improves the E7-specific CD8+ T cell, and increases proinflammatory Th1 and Th17 T cells.

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The E743–77 peptide–pulsed MHC class II semiallogeneic mature BMDC vacci...
(A–C) WT mice were injected s.c. with 1 × 105 TC-1 tumor cells and injected intradermally (i.d.) with either of the E743–77 peptide–pulsed syngeneic WT, MHC class I semiallogeneic bm1, or MHC class II semiallogeneic bm12 LPS-matured BMDC (mBMDC) vaccines 4 times starting 8 days after tumor inoculation at 5-day intervals. (A) Experimental scheme. (B) Average and (C) individual tumor growth of each tumor-bearing mouse. (D–H) The mice noted in B and C were sacrificed 22 days after TC-1 tumor inoculation, and tumors were subjected to flow cytometric analysis of infiltrating CD8+ and E7/H2Db tetramer+ cells and CD4+ T cell subsets in tumors. (D) Representative flow cytometry contour plots for E7/H2Db tetramer+CD8+ T cells. Numbers in the plots indicate the percentage of gated cells. (E) Individual mouse values of tumor weight and (F) E7/H2Db tetramer+CD44+CD8+ T cells, and (G) correlation between tumor-infiltrating E7/H2Db tetramer+CD44+CD8+ T cells (y axis) and tumor weight (x axis) of indicated groups. (H) Individual mouse values of CD4+ T cell subsets. (I and J) WT mice were injected s.c. on the same schedule as A with 1 × 105 TC-1 tumor cells and (I) WT or bm12 mBMDCs without peptide pulsing or (J) E743–77 peptide–pulsed WT mBMDCs mixed with either WT or bm12 mBMDCs. Data are presented as mean ± SEM and represent 3 independent experiments, n = 4–5 (B, C, I, and J) and 8–10 (E–H) per group. Statistical analysis was performed using 2-way (B, I, and J) or 1-way ANOVA (E, F, and H) test with post hoc Tukey’s multiple-comparison correction, or linear regression analysis (G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.