Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake.
Previously, we reported that killing tumor cells in vivo with the HSV thymidine kinase/ganciclovir system generates potent antitumor immunity, determined in part by the mechanism by which the cells die and by the levels of inducible heat shock protein (hsp) expression induced during the process of cell death. Here, we show that induction of hsp70 expression induces an infiltrate of T cells, macrophages, and predominantly dendritic cells (DCs) into the tumors as well as an intratumoral profile of Th1 cytokine expression (IFN-gamma, TNF-alpha, and IL-12) and enhances immunogenicity via a T cell-mediated mechanism. In addition, the protection conferred by hsp70 is both tumor and cell specific. We also demonstrate that hsp70 targets immature APC to make them significantly more able to capture Ags. This is likely to optimize cross-priming of the infiltrating APC with tumor Ags, which are simultaneously being released by the dying cells. In addition, using an Myc epitope-tagged hsp70 expression vector, we present evidence that hsp70 released from dying tumor cells is taken up directly into DCs and may, therefore, be involved in direct chaperoning of Ags into DCs. Taken together, our data suggest that hsp70 induction serves to signal the immune system of the presence of an immunologically relevant (dangerous) situation against which an immune reaction should be raised.
Todryk
S
S
Imperial Cancer Research Fund Laboratory of Molecular Therapy, Imperial Cancer Research Fund Oncology Unit, Imperial College of Science and Medicine, Hammersmith Hospital, London, United Kingdom.
Melcher
A A
AA
Hardwick
N
N
Linardakis
E
E
Bateman
A
A
Colombo
M P
MP
Stoppacciaro
A
A
Vile
R G
RG
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002458:Cell Fractionation; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D016130:Immunophenotyping; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape / Q000276:immunology
D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I