Abstract
To establish a more efficient treatment for immunotherapy against solid tumors, we have evaluated the antitumor effect by coexpression of a chemokine CCL21/secondary lymphoid tissue chemokine and a costimulatory molecule LIGHT in colon carcinoma C26. C26 cells expressing either CCL21 or LIGHT exhibited a significantly reduced tumor growth in vivo, and mice inoculated with these cells showed a prolonged survival, but eventually all these mice died. In contrast, C26 cells expressing both CCL21 and LIGHT exhibited a minimal tumor growth in vivo, and all these mice survived healthily with a tumor remission and consequently acquired a strong protective immunity. A markedly increased infiltration of mature dendritic cells (DCs), and CD8+ T cells was observed in the tumor mass, and their spleen cells showed a greatly enhanced cytotoxic T lymphocyte (CTL) activity against C26 tumor and interferon (IFN)-γ production. Neutralization of IFN-γ or depletion of CD8+ or CD4+ T cells significantly reduced the antitumor activity. These results suggest that the combined treatment with CCL21 and LIGHT is able to induce a synergistic antitumor effect to eradicate tumor completely by greatly enhancing tumor-infiltration of lymphocytes including mature DCs and CD8+ T cells, resulting in markedly augmented CTL activity and IFN-γ production.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- DC:
-
dendritic cell
- SLC:
-
secondary lymphoid tissue chemokine
- APC:
-
antigen-presenting cell
- Th:
-
T helper cell
- CTL:
-
cytotoxic T lymphocyte
- RT:
-
reverse transcriptase
- IRES:
-
internal ribosome entry site
- ATCC:
-
American Type Culture Collection
- mAb:
-
monoclonal antibody
- C26-CCL21:
-
C26 cells transfected with pcDNA3.1-CCL21 cDNA
- C26-LIGHT:
-
C26 cells transfected with pcDNA3.1-LIGHT cDNA
- C26-C+L:
-
C26 cells transfected with pcDNA3.1-LIGHT cDNA/IRES/CCL21 cDNA
- C26-Vector:
-
C26 cells transfected with pcDNA3.1 vector alone
- CD40L:
-
CD40 ligand
References
Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature. 1998;392:245–252.
Nagira M, Imai T, Hieshima K, et al. Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and mapped to chromosome 9p13. J Biol Chem. 1997;272:19518–19524.
Willimann K, Legler DF, Loetscher M, et al. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur J Immunol. 1998;28:2025–2034.
Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT . A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci USA. 1998;95:258–263.
Sallusto F, Mackay CR, Lanzavecchia A . The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol. 2000;18:593–620.
Cyster JG . Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs. J Exp Med. 1999;189:447–450.
Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O . Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J Biol Chem. 1998;273:7118–7122.
Jenh CH, Cox MA, Kaminski H, et al. Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors. J Immunol. 1999;162:3765–3769.
Saeki H, Moore AM, Brown MJ, Hwang ST . Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol. 1999;162:2472–2475.
Mauri DN, Ebner R, Montgomery RI, et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity. 1998;8:21–30.
Morel Y, Schiano de Colella JM, Harrop J, et al. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J Immunol. 2000;165:4397–4404.
Tamada K, Shimozaki K, Chapoval AI, et al. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J Immunol. 2000;164:4105–4110.
Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS . A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem. 1999;274:13733–13736.
Harrop JA, Reddy M, Dede K, et al. Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J Immunol. 1998;161:1786–1794.
Kwon BS, Tan KB, Ni J, et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem. 1997;272:14272–14276.
Salio M, Cella M, Suter M, Lanzavecchia A . Inhibition of dendritic cell maturation by herpes simplex virus. Eur J Immunol. 1999;29:3245–3253.
Murphy M, Walter BN, Pike-Nobile L, et al. Expression of the lymphotoxin beta receptor on follicular stromal cells in human lymphoid tissues. Cell Death Differ. 1998;5:497–505.
Tamada K, Shimozaki K, Chapoval AI, et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat Med. 2000;6:283–289.
Morel Y, Truneh A, Sweet RW, Olive D, Costello RT . The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol. 2001;167:2479–2486.
Sharma S, Stolina M, Luo J, et al. Secondary lymphoid tissue chemokine mediates T cell-dependent antitumor responses in vivo. J Immunol. 2000;164:4558–4563.
Vicari AP, Ait-Yahia S, Chemin K, Mueller A, Zlotnik A, Caux C . Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. J Immunol. 2000;165:1992–2000.
Kirk CJ, Hartigan-O'Connor D, Nickoloff BJ, et al. T cell-dependent antitumor immunity mediated by secondary lymphoid tissue chemokine: augmentation of dendritic cell-based immunotherapy. Cancer Res. 2001;61:2062–2070.
Soto H, Wang W, Strieter RM, et al. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proc Natl Acad Sci USA. 1998;95:8205–8210.
Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T . STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J. 1999;18:4754–4765.
Yoshimoto T, Takahama Y, Wang CR, Yoneto T, Waki S, Nariuchi H . A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection. J Immunol. 1998;160:5500–5505.
Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A . Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol. 1992;148:1280–1285.
Luster AD, Leder P . IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med. 1993;178:1057–1065.
Li Y, Hellstrom KE, Newby SA, Chen L . Costimulation by CD48 and B7-1 induces immunity against poorly immunogenic tumors. J Exp Med. 1996;183:639–644.
Kellermann SA, Hudak S, Oldham ER, Liu YJ, McEvoy LM . The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells. J Immunol. 1999;162:3859–3864.
Gunn MD, Kyuwa S, Tam C, et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med. 1999;189:451–460.
Forster R, Schubel A, Breitfeld D, et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999;99:23–33.
Fan L, Reilly CR, Luo Y, Dorf ME, Lo D . Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol. 2000;164:3955–3959.
Locksley RM, Killeen N, Lenardo MJ . The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501.
Tamada K, Ni J, Zhu G, et al. Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGHT. J Immunol. 2002;168:4832–4835.
Chan VW, Kothakota S, Rohan MC, et al. Secondary lymphoid-tissue chemokine (SLC) is chemotactic for mature dendritic cells. Blood. 1999;93:3610–3616.
Nagira M, Imai T, Yoshida R, et al. A lymphocyte-specific CC chemokine, secondary lymphoid tissue chemokine (SLC), is a highly efficient chemoattractant for B cells and activated T cells. Eur J Immunol. 1998;28:1516–1523.
Tolba KA, Bowers WJ, Muller J, et al. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activity. Cancer Res. 2002;62:6545–6551.
Grewal IS, Flavell RA . CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998;16:111–135.
Sedgwick JD, Riminton DS, Cyster JG, Korner H . Tumor necrosis factor: a master-regulator of leukocyte movement. Immunol Today. 2000;21:110–113.
Albert ML, Sauter B, Bhardwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature. 1998;392:86–89.
Trinchieri G . Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–276.
Macatonia SE, Hosken NA, Litton M, et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995;154:5071–5079.
Cella M, Scheidegger D, Palmer-Lehmann K, et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 1996;184:747–752.
Koch F, Stanzl U, Jennewein P, et al. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J Exp Med. 1996;184:741–746.
Campbell JJ, Bowman EP, Murphy K, et al. 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3beta receptor CCR7. J Cell Biol. 1998;141:1053–1059.
Acknowledgements
We thank Drs T Kitamura and E Takada for kindly providing pMX-IRES/EGFP and technical help, respectively.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by a Grant-in-Aid for Scientific Research on Priority Areas and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.
Rights and permissions
About this article
Cite this article
Hisada, M., Yoshimoto, T., Kamiya, S. et al. Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT. Cancer Gene Ther 11, 280–288 (2004). https://doi.org/10.1038/sj.cgt.7700676
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7700676
Keywords
This article is cited by
-
Exploiting innate immunity for cancer immunotherapy
Molecular Cancer (2023)
-
A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma
Cancer Immunology, Immunotherapy (2018)
-
Immunotargeting and eradication of orthotopic melanoma using a chemokine-enhanced DNA vaccine
Gene Therapy (2013)
-
The anti-tumor effect and increased tregs infiltration mediated by rAAV-SLC vector
Molecular Biology Reports (2013)
-
Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse
BMC Cancer (2010)