¹Department of Dermatology and Skin Science and Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence: Dr Jan P. Dutz, The Skin Care Center, 835 West Tenth Avenue, Vancouver, British Columbia Canada V5Z 4E2. E-mail: dutz@interchange.ubc.ca

Received 25 August 2007; Revised 29 December 2007; Accepted 1 February 2008; Published online 27 March 2008.

Abstract

Malignant melanoma is a potentially fatal skin cancer that is increasing in incidence. Standard chemoimmunotherapy consisting of dacarbazine (DTIC) given with IFN- has had disappointing results. We describe a chemoimmunotherapy protocol for cutaneous melanoma that combines the administration of DTIC with the topical application of CpG oligodinucleotide (ODN). Subcutaneous B16 melanoma tumors in C57BL/6 mice were treated with intraperitoneal injections of DTIC followed by the topical application of CpG-ODN over the tumors. This therapeutic approach abrogated the growth of established tumors and significantly enhanced survival. Topical CpG application was more effective than intratumoral CpG. Cell depletion studies indicated that the antitumor effect was dependent on both CD4⁺ and CD8⁺ cells but not on natural killer (NK) cells. Tumor-specific cytotoxic T-lymphocyte activity was generated in treated animals and was highest in topically treated animals. Immunohistochemical analysis revealed that DTIC, but not CpG, enhanced tumor cell apoptosis. Further, topical CpG induced an expansion of a B220⁺CD8⁺ subset of dendritic cells and a subset of NK1.1⁺ CD11c⁺ cells within the tumors. By enhancing both tumor cell death and local immune activation, DTIC/topical CpG chemoimmunotherapy induced an effective T-cell-dependent host–immune response against melanoma.