The CC chemokine CK beta-11/MIP-3 beta/ELC/Exodus 3 mediates tumor rejection of murine breast cancer cells through NK cells.
CK beta-11 chemoattracts T cells, B cells, dendritic cells, macrophage progenitors, and NK cells and facilitates dendritic cell and T cell interactions in secondary lymphoid tissues. We hypothesized that expression of CK beta-11 in tumor cells may generate antitumor immunity through these interactions. After transduction with the retroviral vector L(CK beta 11)SN, the murine breast cancer cell line C3L5 (C3L5-CK beta 11) showed expression of retroviral mRNA by Northern analysis and production of functional CK beta-11 by chemotaxis of human NK cells to C3L5-CK beta 11 supernatant. Only 10% of mice injected with C3L5-CK beta 11 developed tumors, compared with 100% of mice injected with a transduced control C3L5 line (C3L5-G1N). Importantly, the in vitro growth characteristics of the CK beta-11-transduced cell line were unaffected, suggesting the difference in growth in vivo was a result of chemokine production. Vaccination with C3L5-CK beta 11 partially protected animals from parental C3L5 challenge. Immunodepletion with anti-asialo-GM1 or anti-CD4 during C3L5-CK beta 11 vaccination significantly reduced CK beta-11 antitumor activity compared with control and anti-CD8-treated groups. Splenocytes from NK-depleted animals transferred the acquired immunity generated with C3L5-CK beta 11 vaccination, while splenocytes from the CD4-depleted animals did not. These results indicate, for the first time, that expression of CK beta-11 in a breast cancer cell line mediates rejection of the transduced tumor through a mechanism involving NK and CD4+ cells. Furthermore, CK beta-11-transduced tumor cells generate long-term antitumor immunity that requires CD4+ cells. These studies demonstrate the potential role of CK beta-11 as an adjuvant in stimulating antitumor responses.
Braun
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Departments ofMicrobiology/Immunology and Medicine (Hematology/Oncology), and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. stephen_braun@hms.harvard.edu
Chen
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Foster
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Kim
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Hromas
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Kaplan
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Broxmeyer
H E
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Cornetta
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D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000276:immunology; D017710:Lymphocyte Transfusion; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D014407:Tumor Cells, Cultured
C515460:CCL19 protein, human; D019496:Cancer Vaccines; C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D007106:Immune Sera