This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Novak, L. Articles by Alexeev, V. Search for Related Content PubMed PubMed Citation Articles by Novak, L. Articles by Alexeev, V. Related Collections Early Detection Early Detection: Biomarkers: Discovery, Methodology, Validation Preclinical Intervention Preclinical Intervention: In Vivo (Animals): Drugs, Nutritional Interventions, Mechanisms

Research Articles: Therapeutics, Targets, and Development

Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication

Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Vitali Alexeev, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, 233 South 10th Street, BLSB, Room 326, Philadelphia, PA 19107. Phone: 215-503-4835; Fax: 215-503-5788. E-mail: vitali.alexeev{at}jefferson.edu

Abstract

Previous studies have shown that secondary lymphoid chemokine, CCL21, can be used for modulation of tumor-specific immune responses. Here, using B16F0 melanoma cells stably expressing CCL21 under the control of cytomegalovirus and ubiquitin promoters, we showed that CCL21-activated immune responses depend on the amount of melanoma-derived chemokine, which, in turn, depends on the strength of the promoter. We showed that ubiquitin promoter–driven expression of CCL21 enabled massive infiltration of tumors with CD4⁺CD25^–, CD8⁺ T lymphocytes, and CD11c⁺ dendritic cells, and consequent activation of cellular and humoral immune responses sufficient for complete rejection of CCL21-positive melanomas within 3 weeks in all tumor-inoculated mice. Mice that rejected CCL21-positive tumors acquired protective immunity against melanoma, which was transferable to naive mice via splenocytes and central memory T cells. Moreover, melanoma-derived CCL21 facilitated immune-mediated remission of preestablished, distant wild-type melanomas. Overall, these results suggest that elevated levels of tumor-derived CCL21 are required for the activation of strong melanoma-specific immune responses and generation of protective immunologic memory. They also open new perspectives for the development of novel vaccination strategies against melanoma, which use intratumoral delivery of the optimized CCL21-encoding vectors in conjunction with DNA-based vaccines. [Mol Cancer Ther 2007;6(6):1–10]

Grant support: Jefferson Medical College (V. Alexeev) and American Skin Association medical student grant (L. Novak).

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.

Received 11/15/06; revised 4/ 9/07; accepted 5/ 1/07.