Tumor cells engineered with IL-12 and IL-15 genes induce protective antibody responses in nude mice.
IL-12 and IL-15 stimulate T, B, and NK cell functions through independent mechanisms, and cooperative effects of these cytokines have been reported. The human MHC class I-negative small cell lung cancer cell line, N592, genetically engineered to secrete IL-15, N592/IL-15, showed a reduced tumor growth rate, while N592 cells engineered with IL-12, N592/IL-12, grew similarly to the wild-type N592, N592 parental cells (N592pc), in nude mice. However, N592 cells coexpressing both cytokines, N592/IL-12/IL-15 cells, were completely rejected by 100% of nude mice. Here we show that 60% of nude mice rejecting N592/IL-12/IL-15 cells were resistant to N592pc rechallenge. SCID mice rejected N592/IL-12/IL-15 cells, but did not develop resistance to N592pc rechallenge, suggesting a role of Ab responses. Among nude mice rejecting N592/IL-12/IL-15 cells, those developing resistance to N592pc rechallenge had significantly higher titers of anti-N592 IgG2b Abs than nonresistant nude mice. Induction of an Ig class switch in nude mice was related to the expression of IFN-gamma and CD40 ligand in the draining lymph nodes. An IgG2b, anti-N592 mAb, derived from N592/IL-12/IL-15-immunized nude mice splenocytes induced significant protection against N592pc, while an IgM mAb was ineffective. The protective IgG2b mAb, but not the IgM mAb, triggered Ab-dependent cell-mediated cytotoxicity by nude mouse splenocytes against N592pc. These data indicate that IL-12 and IL-15 synergistically trigger innate, immunity-mediated, anti-tumor effects, resulting in cytotoxic IgG Ab responses in T cell-deficient mice. Protective Ab responses may relate to both direct actions of IL-12 and IL-15 on B cells and to the activation of an innate immunity-B cell cross-talk.
Orengo
Anna Maria
AM
Laboratory of Immunopharmacology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Di Carlo
Emma
E
Comes
Alberto
A
Fabbi
Marina
M
Piazza
Tiziana
T
Cilli
Michele
M
Musiani
Piero
P
Ferrini
Silvano
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D000912:Antibodies, Neoplasm / Q000096:biosynthesis* / Q000097:blood / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004357:Drug Synergism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006801:Humans; D006825:Hybridomas; D007113:Immunity, Innate / Q000235:genetics; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*; D019409:Interleukin-15 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015202:Protein Engineering / Q000379:methods*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007074:Immunoglobulin G; D019409:Interleukin-15; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma