Taking lessons from dendritic cells: multiple xenogeneic ligands for leukocyte integrins have the potential to stimulate anti-tumor immunity.
Expression of large numbers of different costimulatory integrin ligands (CILs) attributes dendritic cells with an ability to induce primary anti-tumor immune responses. Here, we show that optimized gene transfer of the xenogeneic (human) CILs VCAM-1, MAdCAM-1 and ICAM-1 causes rapid and complete rejection of established mouse EL-4 tumors, and generates prolonged systemic anti-tumor immunity; whereas human E-cadherin weakly slows tumor growth. In each case the immune response was mediated by CD8+ T cells and NK cells, accompanied by augmented tumor-specific cytolytic T cell (CTL) activity involving both the perforin and Fas-ligand pathways. Adoptive transfer of splenocytes from cured mice rapidly cleared established tumors in recipients. The mechanism for CIL-mediated immunity is unknown, but may involve CTL-facilitated tumor lysis, since CTLs were generally twice as efficient at killing CIL-transfected tumor cells than parental tumor cells. Optimized CIL-based gene therapy may provide an approach to complement or replace conventional DC adoptive cell therapy for suppressing tumor growth.
Kanwar
J
J
Department of Molecular Medicine, School of Medicine and Health Science, University of Auckland, Auckland, New Zealand.
Berg
R
R
Lehnert
K
K
Krissansen
G
G
D000818:Animals; D015478:Antigens, Heterophile / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016023:Integrins / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D014407:Tumor Cells, Cultured
D015478:Antigens, Heterophile; D015815:Cell Adhesion Molecules; D016023:Integrins; D008024:Ligands