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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References
Pardoll DM . Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol 2002; 2: 227–238.
He T, Zong S, Wu X, Wei Y, Xiang J . CD4+ T cell acquisition of the bystander pMHC I colocalizing in the same immunological synapse comprising pMHC II and costimulatory CD40, CD54, CD80, OX40L, and 41BBL. Biochem Biophys Res Commun 2007; 362: 822–828.
Padhan K, Varma R . Immunological synapse: a multi-protein signalling cellular apparatus for controlling gene expression. Immunology 2010; 129: 322–328.
Kapsenberg ML . Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 2003; 3: 984–993.
Curtsinger JM, Mescher MF . Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 2010; 22: 333–340.
Pulendran B . Modulating TH1/TH2 responses with microbes, dendritic cells, and pathogen recognition receptors. Immunol Res 2004; 29: 187–196.
Guermonprez P, Saveanu L, Kleijmeer M, Davoust J, van Endert P, Amigorena S . ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 2003; 425: 397–402.
Kleijmeer MJ, Escola JM, UytdeHaag FG, Jakobson E, Griffith JM, Osterhaus AD et al. Antigen loading of MHC class I molecules in the endocytic tract. Traffic 2001; 2: 124–137.
Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998; 4: 594–600.
Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ . Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 2000; 113( Pt 19): 3365–3374.
Hao S, Bai O, Yuan J, Qureshi M, Xiang J . Dendritic cell-derived exosomes stimulate stronger CD8+ CTL responses and antitumor immunity than tumor cell-derived exosomes. Cell Mol Immunol 2006; 3: 205–211.
Hao S, Liu Y, Yuan J, Zhang X, He T, Wu X et al. Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses. J Immunol 2007; 179: 2731–2740.
Liu Y, Wenger RH, Zhao M, Nielsen PJ . Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes. J Exp Med 1997; 185: 251–262.
Suresh M, Whitmire JK, Harrington LE, Larsen CP, Pearson TC, Altman JD et al. Role of CD28-B7 interactions in generation and maintenance of CD8 T cell memory. J Immunol 2001; 167: 5565–5573.
Pulle G, Vidric M, Watts TH . IL-15-dependent induction of 4-1BB promotes antigen-independent CD8 memory T cell survival. J Immunol 2006; 176: 2739–2748.
Mousavi SF, Soroosh P, Takahashi T, Yoshikai Y, Shen H, Lefrancois L et al. OX40 costimulatory signals potentiate the memory commitment of effector CD8+ T cells. J Immunol 2008; 181: 5990–6001.
Hernandez MG, Shen L, Rock KL . CD40 on APCs is needed for optimal programming, maintenance, and recall of CD8+ T cell memory even in the absence of CD4+ T cell help. J Immunol 2008; 180: 4382–4390.
Boesteanu AC, Katsikis PD . Memory T cells need CD28 costimulation to remember. Semin Immunol 2009; 21: 69–77.
Xiang J, Huang H, Liu Y . A new dynamic model of CD8+ T effector cell responses via CD4+ T helper-antigen-presenting cells. J Immunol 2005; 174: 7497–7505.
Xiang J, Qi Y, Chen Y . Inhibition of established tumor growth in syngeneic mice by local inoculation of engineered mouse myeloma cells secreting a recombinant fusion protein RM4/TNF. Cancer Gene Ther 1997; 4: 353–358.
Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ . T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 1998; 393: 480–483.
Munroe ME, Bishop GA . A costimulatory function for T cell CD40. J Immunol 2007; 178: 671–682.
Bourgeois C, Rocha B, Tanchot C . A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 2002; 297: 2060–2063.
Palucka K, Ueno H, Banchereau J . Recent developments in cancer vaccines. J Immunol 2011; 186: 1325–1331.
Steinman RM . Some active areas of DC research and their medical potential. Eur J Immunol 2010; 40: 2085–2088.
Zou W . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.
Baecher-Allan C, Anderson DE . Immune regulation in tumor-bearing hosts. Curr Opin Immunol 2006; 18: 214–219.
Gross S, Walden P . Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunol Lett 2008; 116: 7–14.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942–949.
Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F . Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005; 65: 2457–2464.
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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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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DOI: https://doi.org/10.1038/cmi.2012.37
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