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 1

Syngeneic and semiallogeneic BMDCs present H2Db-restricted peptide to CD8+ T cells similarly, but the gp10025–33 peptide–pulsed MHC class II semiallogeneic BMDC vaccine is superior for delaying of B16-F10 tumor growth and improves antigen-specific CD8+ T cell and proinflammatory Th1 responses.

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Syngeneic and semiallogeneic BMDCs present H2Db-restricted peptide to CD...
(A) Schematic overview of H2Db-restricted peptide pulsed syngeneic WT, MHC class I semiallogeneic bm1, or MHC class II semiallogeneic bm12 BMDC vaccine experiments in mouse models. (B) In vitro IFN-γ production of isolated CD8+ T cells from naive Pmel-1 mice stimulated with titrated LPS-matured BMDCs (mBMDCs) pulsed with or without gp10025–33 peptide by ELISA. Isolated splenic Pmel-1 CD8+ T cells (1 × 105) were cocultured with different ratios of the WT, bm1, or bm12 mBMDCs with or without 20 μg/mL gp10025–33 peptide pulsing in 200 μL/well in 96-well round-bottom plates for 24 hours. mBMDCs, Pmel-1 CD8+ T cells, or hgp100 alone were controls. (C–E) WT mice were injected s.c. with 1 × 105 B16-F10 tumor cells, and mice were injected intradermally (i.d.) with either of the gp10025–33-pulsed WT, bm1, or bm12 mBMDC vaccines 3 times starting 4 days after tumor inoculation at 5-day intervals. (C) Experimental scheme and (D) average and (E) individual tumor growth. The mice noted in D and E were sacrificed 14 days after B16-F10 tumor inoculation, and tumors were subjected to flow cytometric analysis of infiltrating CD8+ and hgp100/H2Db tetramer+ cells and CD4+ T cell subsets. Individual mouse values of (F) tumor weight, (G) hgp100/H2Db tetramer+CD69+CD8+ T cells, and (H) Th1 cell in tumors. Data are presented as mean ± SEM and represent 3 independent experiments, n = 3 (B), 4–5 (D and E) and 6–9 (F–H) per group. Statistical analysis was performed using 2-way (D) or 1-way (E, F, and H) ANOVA test with post hoc Tukey’s multiple-comparison correction. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.