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,
* Molecular Medicine Program,
Department of Immunology, and
Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, MN 55905; and
Cancer Research U.K. Clinical Centre, St. James University Hospital, Leeds, United Kingdom
Previously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-
. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.
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 the Mayo Foundation and by National Institutes of Health Grants R0194180 and P50CA91956.
2 L.S.-P. and T.K. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Richard G. Vile, Molecular Medicine Program, Guggenheim 1836, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55902. E-mail address: vile.richard{at}mayo.edu
4 Abbreviations used in this paper: HSVtk, HSV thymidine kinase; GCV, ganciclovir; hsp70, heat shock protein 70; LN, lymph node; MHC-II, MHC class II.
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