Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas

Luis Sanchez-Perez, Timothy Kottke, Gregory A. Daniels, Rosa Maria Diaz, Jill Thompson, Jose Pulido, Alan Melcher, Richard G. Vile

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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-α. 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 core 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.

Original languageEnglish (US)
Pages (from-to)4168-4177
Number of pages10
JournalJournal of Immunology
Issue number6
StatePublished - Sep 15 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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