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A novel T cell-based vaccine capable of stimulating long-term functional CTL memory against B16 melanoma via CD40L signaling

Abstract

The ultimate goal of antitumor vaccines is to develop memory CD8+ cytotoxic T lymphocytes (CTLs), which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin (OVA)-specific CD4+ T cell-based (OVA-TEXO) vaccine generated using OVA-pulsed dendritic cell (DCOVA)-released exosomes (EXOOVA) stimulate CTL responses via IL-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type (WT) C57BL/6 and gene-knockout mice with WT CD4+ OVA-TEXO cells or OVA-TEXO cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2Kb/OVA257–264 tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-10OVA. We demonstrated that CD4+ OVA-TEXO cells stimulated more efficient CTL responses compared to DCOVA. By assessing primary and recall CTL responses in mice immunized with OVA-TEXO or with OVA-TEXO lacking the costimulatory molecules CD40L, 4-1BBL or OX40L, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-TEXO. Interestingly, CD40L, but not 4-1BBL or OX40L, plays a crucial role in the development of functional memory CTLs against BL6-10OVA tumors. Overall, this work suggests that a novel CD4+ T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination.

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Acknowledgements

This research was supported by research grants from the Canadian Institutes of Health Research and Canadian Breast Cancer Foundation. Yufeng Xie and Lu Wang were supported by Postdoctoral Fellowships from the Saskatchewan Health Research Foundation and the Scholarship Council of Chinese Education Ministry. We would also like to extend our appreciation to Mark Boyd for his help with the flow cytometry.

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Correspondence to Jim Xiang.

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Xie, Y., Wang, L., Freywald, A. et al. A novel T cell-based vaccine capable of stimulating long-term functional CTL memory against B16 melanoma via CD40L signaling. Cell Mol Immunol 10, 72–77 (2013). https://doi.org/10.1038/cmi.2012.37

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