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* Center for the Molecular Stress Response, Department of Medicine, Boston University Medical Center, Boston, MA 02118;
Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and
Laboratory of Cellular Biochemistry, RIKEN (Institute of Physical and Chemical Research), Wako-shi, Saitama, Japan
Heat shock protein (HSP) 70 isolated from tumor-dendritic cell (DC) fusions (HSP70.PC-F) induces potent antitumor immunity and prevents growth of such tumors. In the present study, we have examined mechanisms underlying such antitumor activity of the HSP70.PC-F vaccine. The degree of antitumor immunity induced by HSP70.PC-F depended on intact TLR signaling in immunized animals, and mice in which the tlr2 and tlr4 genes were both inactivated did not respond to the vaccine. The reduced responses to HSP70.PC-F vaccine in such tlr knockout mice were restored by immunization of animals with HSP70.PC-F-pulsed wild-type DC, indicating a key role for this cell type in HSP70.PC-F-mediated immunity. Our studies also indicate a role for the scavenger receptor expressed by endothelial cells-1 (SREC-1) in antitumor immunity induced by HSP70.PC-F. These two receptor types appeared functionally interdependent, as indicated by the finding that tlr2 and tlr4 knockout decreases HSP70 binding in double-knockout DC and reduces SREC-1 expression. In addition, TLR-dependent, tumor cell killing was suppressed by SREC-1 knockdown in DC, suggesting a significant role for this receptor in HSP70.PC-F-mediated tumor immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Research Grants R01CA047407 (to S.K.C.), R01CA094397 (to S.K.C.), and R01CA119045 (to S.K.C.); the U.S. Department of Defense Breast Cancer Research programs (to J.G.); and the Ellison Foundation (to J.G.).
2 Address correspondence and reprint requests to Dr. Stuart K. Calderwood, Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215; E-mail address: scalderw{at}bidmc.harvard.edu or Dr. Jianlin Gong, Boston University School of Medicine, 650 Albany Street, Room 309, Boston, MA 02118; E-mail address: jgong{at}bu.edu
3 Abbreviations used in this paper: HSP, heat shock protein; DC, dendritic cell; KO, knockout; LN, lymph node; LNC, LN cell; LOX-1, lectin-like oxidized low-density lipoprotein receptor 1; mBSA, maleylated BSA; shRNA, small hairpin RNA; SREC-1, scavenger receptor expressed by endothelial cells-1; WT, wild type.
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