Gene therapy to manipulate effector T cell trafficking to tumors for immunotherapy.
Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the "visibility" of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.
Gough
Michael
M
Molecular Medicine Program and Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. michael.gough@providence.org
Crittenden
Marka
M
Thanarajasingam
Uma
U
Sanchez-Perez
Luis
L
Thompson
Jill
J
Jevremovic
Dragan
D
Vile
Richard
R
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000502:physiology; D019742:Chemokines, CC / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics* / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016219:Immunotherapy, Adoptive / Q000379:methods; D018836:Inflammation Mediators / Q000502:physiology; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019713:Receptors, CCR5 / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5