Cooperative effects of Mycobacterium tuberculosis Ag38 gene transduction and interleukin 12 in vaccination against spontaneous tumor development in proto-neu transgenic mice.
An approach to stimulating an immune response against tumors is to transduce tumor cells with bacterial genes, which represent a "danger signal" and can induce a wide immune response. Mycobacterium tuberculosis genes and their encoded proteins play a pivotal role in linking innate and cell-mediated adaptive immunity and represent ideal candidates as immune adjuvants for tumor vaccines. The efficacy of a cancer vaccine, obtained by transduction of a mammary tumor cell line with the M. tuberculosis Ag38 gene, was investigated in female mice transgenically expressing the rat HER-2/neu proto-oncogene. These mice spontaneously develop stochastic mammary tumors after a long latency period. The onset of spontaneous mammary tumors was significantly delayed in mice vaccinated with Ag38-transduced cells but not in mice vaccinated with nontransduced cells as compared with untreated mice. Protection from spontaneous tumor development was increased when mice were vaccinated with the mycobacterium gene-transduced vaccine plus a systemic administration of interleukin 12 (IL-12) at a low dose. Mice vaccinated with nontransduced cells plus IL-12 developed tumors, with only a slight delay in tumor appearance as compared with the control group. Lymphocytes obtained from lymph nodes of mice vaccinated with transduced cells secreted high levels of IFN-gamma. CD3+CD8+ spleen cells derived from these mice responded to the tumor with IFN-gamma production. These data indicate the efficacy of a short-term protocol of vaccinations exploiting the adjuvant potency of a M. tuberculosis gene and low doses of IL-12 in a model of stochastic development of mammary tumors. This adjuvant approach may represent a promising immunotherapeutic strategy for cancer immunization.
Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
L
L
Sfondrini
M
M
Rodolfo
M
M
Singh
M P
MP
Colombo
M I
MI
Colnaghi
S
S
Ménard
A
A
Balsari
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019496:Cancer Vaccines; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis; D008074:Lipoproteins / Q000235:genetics*; D008198:Lymph Nodes / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D019496:Cancer Vaccines; D016207:Cytokines; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D008074:Lipoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C075966:Ag38 antigen, Mycobacterium tuberculosis