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

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...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2007-06, Vol.6 (6), p.1755-1764
Main Authors: Novak, Laura, Igoucheva, Olga, Cho, Stephanie, Alexeev, Vitali
Format: Article
Language:English
Subjects:
Animals
Antibody Formation
Base Sequence
Chemokine CCL21
Chemokines, CC - physiology
Cytomegalovirus
DNA Primers
immune response
Immunity, Cellular
immunotherapy
melanoma
Melanoma, Experimental - immunology
Mice
secondary lymphoid chemokine
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Summary: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]
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-06-0709