TCR vaccines against a murine T cell lymphoma: a primary role for antibodies of the IgG2c class in tumor protection.
Tumor-associated proteins can act as effective immunotherapeutic targets. Immunization with tumor TCR protein conjugated to the immunogenic protein keyhole limpet hemocyanin (KLH) protects mice from tumor challenge with the murine T cell lymphoma C6VL. The immune mechanisms responsible for this tumor protection are of interest for designing more effective vaccine strategies. Previous studies using depletion experiments had suggested a CD8-mediated component of protection induced by TCR-KLH vaccines. In this study we used CD8alpha knockout, micro MT, and FcgammaR knockout mice to investigate the relative roles of CD8+ T cells and Ab in protective immunity induced by TCR-KLH immunization. We found that CD8+ T cells are not required for tumor protection, although they may contribute to protection. Vaccine-induced Abs are sufficient to mediate protection against this murine T cell lymphoma through an FcR-dependent mechanism. This was confirmed with Ab transfers, which protect challenged mice. Additionally, recombinase-activating gene 1(-/-) splenocytes can mediate Ab-dependent cellular cytotoxicity against this tumor in the presence of bound anti-TCR Abs. IFN-gamma knockout mice demonstrated a requirement for IFN-gamma, probably via generation of IgG2c Abs, in vaccine-induced tumor protection. IFN-gamma knockout mice were not protected by immunization and had a severe impairment in IgG2c Ab production in response to immunization. Although mock-depleted anti-TCR Abs could transfer tumor protection, IgG2c-deficient anti-TCR Abs were unable to transfer tumor protection to wild-type mice. These results suggest that TCR-KLH vaccine-induced tumor protection in the C6VL system is primarily attributable to the induction of IgG2c Abs and humoral immunity.
Lambert
Stacie L
SL
Division of Oncology and Program in Immunology, Stanford University School of Medicine, 369 Campus Drive, Stanford, CA 94305, USA.
Okada
Craig Y
CY
Levy
Ronald
R
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000502:physiology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000502:physiology*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000008:administration & dosage / Q000276:immunology*; D011961:Receptors, Fc / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011961:Receptors, Fc; D018664:Interleukin-12; D007371:Interferon-gamma; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin