In vivo gene transfer of CD40 ligand into colon cancer cells induces local production of cytokines and chemokines, tumor eradication and protective antitumor immunity.
The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells, is essential for the initiation of cell-mediated and humoral immune responses. In this study, we investigated the antitumor effect of in vivo gene transfer of CD40L to tumor cells using an adenoviral vector (AdCMVmCD40L) in a murine CT-26 colon cancer model. We found that injection of AdCMVmCD40L caused tumor regression in a dose-dependent manner. A complete regression of tumor was observed in 81% of mice treated with 10(9) p.f.u. of AdCMVmCD40L. The antitumor effect induced by CD40L was mediated by CD8+ T cells and was associated with the generation of tumor-specific cytolytic T lymphocytes (CTL). Animals that eradicated the tumor were protected against tumor cell rechallenge, and both CD4+ and CD8+ T cells were involved in specific protective immunity. Treatment with AdCMVmCD40L in one tumor nodule also caused complete regression of established tumors at distant sites. The antitumor effect elicited by AdCMVmCD40L was associated with the intratumoral production of IL-12 and IFN-gamma and with an increased intratumoral expression of chemokines such as MIP- 1alpha, MIP-1beta, MIP-2, RANTES, and eotaxin. These data demonstrate that intratumoral injection of AdCMVmCD40L induces a powerful cascade of chemokines and cytokines in the tumor mass and stimulates an efficient antitumor immunity leading to regression of established colon cancer and protection against tumor cell rechallenge.
Sun
Y
Y
Department of Internal Medicine, School of Medicine, University of Navarra, Pamplona, Spain.
Peng
D
D
Lecanda
J
J
Schmitz
V
V
Barajas
M
M
Qian
C
C
Prieto
J
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000032:analysis; D054426:Chemokine CXCL2; D019742:Chemokines, CC; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000032:analysis; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054426:Chemokine CXCL2; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D015846:Monokines; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma