Abstract
Attenuated Listeria monocytogenes (LM) is a promising candidate vector for the delivery of cancer vaccines. After phagocytosis by antigen-presenting cells, this bacterium stimulates the major histocompatibility complex (MHC)-I and MHC-II pathways and induces the proliferation of antigen-specific T lymphocytes. A new strategy involving genetic modification of the replication-deficient LM strain ΔdalΔdat (Lmdd) to express and secrete human CD24 protein has been developed. CD24 is a hepatic cancer stem cell biomarker that is closely associated with apoptosis, metastasis and recurrence of hepatocellular carcinoma (HCC). After intravenous administration in mice, Lmdd-CD24 was distributed primarily in the spleen and liver and did not cause severe organ injury. Lmdd-CD24 effectively increased the number of interferon (IFN)-γ-producing CD8+ T cells and IFN-γ secretion. Lmdd-CD24 also enhanced the number of IL-4- and IL-10-producing T helper 2 cells. The efficacy of the Lmdd-CD24 vaccine was further investigated against Hepa1–6-CD24 tumors, which were inguinally inoculated into mice. Lmdd-CD24 significantly reduced the tumor size in mice and increased their survival. Notably, a reduction of T regulatory cell (Treg) numbers and an enhancement of specific CD8+ T-cell activity were observed in the tumor-infiltrating lymphocytes (TILs). These results suggest a potential application of the Lmdd-CD24 vaccine against HCC.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation (81072029 to BS, 30901750 and 81272322 to YC and 81201528 to RJ), the National Basic Research Program of China (2012CB910800 to BS), the Major Research Plan of the National Natural Science Foundation (91029721 to BS), the Natural Science Foundation of Jiangsu Province (BK2010532 to YC), the China Postdoctoral Science Foundation-funded Project (20090461133 to YC), the Jiangsu Planned Projects for Postdoctoral Research Funds (1001028B to YC) and the Jiangsu Province Laboratory of Pathogen Biology (11BYKF02 to QS).
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Yang, Y., Hou, J., Lin, Z. et al. Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells. Cell Mol Immunol 11, 184–196 (2014). https://doi.org/10.1038/cmi.2013.64
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DOI: https://doi.org/10.1038/cmi.2013.64
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