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National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, People’s Republic of China
Extracellular heat shock proteins (HSP) can activate dendritic cells (DC) and monocytes/macrophages, and HSP derived from tumor cells have been regarded as potent adjuvant facilitating presentation of tumor Ags and induction of antitumor immunity. However, the roles and the underlying mechanisms of releasable HSP in the induction of antitumor immunity have not been fully elucidated. In this study, we report that heat stress can induce the release of various HSP from tumor cells, which, in turn, activate tumor cells to produce chemokines for chemoattraction of DC and T cells via TLR4 signaling pathway. In vivo, we find that the infiltration and function of DC and T cells within tumor after local hyperthermia are increased significantly. We also provide evidence that HSP70 proteins released by tumor cells and TLR4 expressed by tumor cells/DC are essential for the chemoattraction of DC/T cells and for the subsequent induction of tumor-specific antitumor immunity. Therefore, our study suggests that heat stress-induced releasable HSP70 proteins from tumor cells play important roles in the initiation of antitumor immunity by inducing tumor cell production of chemokines and by activating the chemoattracted DC via TLR4 pathway.
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1 This work was supported by grants from Foundation for the Author of National Excellent Doctoral Dissertation of China (200775), National Natural Science Foundation of China (30572122, 30771118, and 30721091), National Key Basic Research Program of China (2007CB512403), and Shanghai Committee of Science and Technology (07QA14067).
2 T.C. and J.G. contributed equally to this work.
3 Current address: Department of Renal Cancer and Melanoma, Beijing Cancer Hospital and Institute, Beijing, People’s Republic of China.
4 Address correspondence and reprint requests to Dr. Xuetao Cao, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People’s Republic of China. E-mail address: caoxt{at}public3.sta.net.cn
5 Abbreviations used in this paper: BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; HS, heat stress; HSC70, cognate HSP70; HSP70i, inducible HSP70; HSP, heat shock protein; HT, hyperthermia; MDSC, myeloid-derived suppressor cell; RNAi, RNA interference; siRNA, small interfering RNA; SN, culture supernatant; TIMC, tumor-infiltrating mononuclear cell; Treg, regulatory T cell; WCL, whole-cell lysate; TRIF, Toll/IL-1R domain-containing adapter inducing IFNβ.
6 The online version of this article contains supplemental material.
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  C. A. Martin, D. L. Kurkowski, A. M. Valentino, and F. Santiago-Schwarz Increased Intracellular, Cell Surface, and Secreted Inducible Heat Shock Protein 70 Responses Are Triggered during the Monocyte to Dendritic Cell (DC) Transition by Cytokines Independently of Heat Stress and Infection and May Positively Regulate DC Growth J. Immunol., July 1, 2009; 183(1): 388 - 399. [Abstract] [Full Text] [PDF]
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