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A novel t cell-based vaccine capable of stimulating long-term functional CtL memory against B 16 melanoma via CD40L signaling

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cellular & Molecular Immunology 2013年第1期10卷 72-77页

作者： Yufeng Xie Lu Wang Andrew Freywald Mabood Qureshi Yue Chen Jim Xiang Saskatchewan Cancer Agency Department of Oncology University of Saskatchewan Saskatoon Saskatchewan Canada Department of Pathology University ofSaskatchewan Saskatoon Saskatchewan Canada and Department of Epidemiology and Community Medicine University of Ottawa Ottawa Ont. Canada Xie and Wang contributed equally to this study.

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） C57BIJ6 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/ 0VA257_264 tetramer and FItC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-1OovA. 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 CD4OL, 4-1BBL or OX4OL, we demonstrated that these costimulatory signals are dispensable for CtL priming by OVA-tExo. Interestingly, CD4OL, but not 4-1BBL or OX4OL, plays a crucial role in the development of functional memory CtLs against BL6-1OovA 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.

关键词： antitumor immunity CD4OL memory CtL t cell-based vaccine

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transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44＋CD62Lhigh IL-7R＋ CtLs with up- and downregulation of anti- and pro-apoptosis genes

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cellular & Molecular Immunology 2015年第4期12卷 456-465页

作者： Rong Wang Andrew Freywald Yue Chen Jianqing Xu Xin tan Jim Xiang Cancer Research Unit Saskatchewan Cancer Agency Saskatoon Saskatchewan Canada Department of Oncology University of Saskatchewan Saskatoon Saskatchewan Canada Department of Pathology University of Saskatchewan Saskatoon Saskatchewan Canada Department of Epidemiology and Community Health University of Ottawa Canada Shanghai Public Health Clinical Center Fudan University Shanghai China School of Life Science Beijing Institute of Technology Beijing China

Human immunodeficiency virus type-1 （HIV-1）-specific dendritic cell （DC） vaccines have been used in clinical trials. However, they have been found to only induce some degree of immune responses in these studies. We previously demonstrated that the HIV-1 Gag-specific Gag-texo vaccine stimulated Gag-specific effector CD8＋ cytotoxic t lymphocyte （CtL） responses, leading to completely protective, but very limited, therapeutic immunity. In this study, we constructed a recombinant adenoviral vector, adenovirus （AdV）4-1BBL, which expressed mouse 4-1BB ligand （4-1BBL）, and generated transgenic 4-1BBL-engineered OVA-texo/4.1BSL and Gag-texo/4.1BSL vaccines by transfecting ovalbumin （OVA）-texo and Gag-＇rexo cells with AdV4.1BBL, respectively. We demonstrate that the OVA-specific OVA-texo/*** vaccine stimulates more efficient OVA-specific CtL responses （3.26%） compared to OVA-texo-activated responses （1.98%） in wild-type C57BIJ6 mice and the control OVA-teXO/Nu, vaccine without transgenic 4-1BBL expression, leading to enhanced therapeutic immunity against 6-day established OVA-expressing B16 melanoma BL6-1OovA cells. OVA-texo/4.1BBL-stimulated CtLs, which have a CD44＋CD62Lhigh IL-7R＋ phenotype, are likely memory CtL precursors, demonstrating prolonged survival and enhanced differentiation into memory CtLs with functional recall responses and long-term immunity against BL6-1OovA melanoma. In addition, we demonstrate that OVA-texo/4_ZBBL-Stimulated CtLs up- and downregulate the expression of anti-apoptosis （Bcl2110, Naipl, No13, Pak7 and tnfrsfllb） and pro-apoptosis （Casp12, trp63 and trp73） genes, respectively, by Rt2 Profiler PCR array analysis. Importantly, the Gag-specific Gag-texo/4.1BBL vaccine also stimulates more efficient Gag-specific therapeutic and long-term immunity against HLA-A2/Gag-expressing B 16 melanoma BL6-1OGag/A2 cells than the control Gag-teXO/NuH vaccine in transgenic HLA-A2 mice. taken together, our novel Gag-texo/4-ZBBL vaccine, which is capable of st

关键词： 4-1BBL Gag HLA-A2 mice t cell-based vaccine therapeutic immunity

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