Mini ReviewInterleukin-12 in anti-tumor immunity and immunotherapy
Section snippets
Interleukin-12 (IL-12), its receptor, and its biological functions
Interleukin-12 (IL-12) is a cytokine that plays an essential role in the interaction between the innate and adaptive arms of immunity [1]. Produced by phagocytic cells, B cells, dendritic cells and possibly other accessory cells following the encounter with infectious agents, IL-12 acts on T cells and NK cells by enhancing generation and activity of cytotoxic lymphocytes and inducing proliferation and production of cytokines, especially IFN-γ. IL-12 is also the major cytokine responsible for
The B16 melanoma model
Several reports have shown that IL-12 has a strong anti-tumor effect against the B16 melanoma and its variants. Discrepant results obtained using metastatic B16F10 are probably dependent on the dose and timing of IL-12 injection. For example, experiments performed in bg/bg [12] and in Jα281–/– [13] mice did not supported a role for NK cells, whereas the experiments in perforin and RAG2 double KO mice strongly suggested an essential role for NK cells [14]. Using strains of mice deficient for
The C26 colon carcinoma model
The transplantable BALB/c colon carcinoma C26 tumor has been widely utilized for the study of the anti-tumor activity of IL-12. Systemic administered IL-12 has no effect against the subcutaneous (s.c.) growth of injected C26 tumor, but greatly reduces the liver metastases induced by intrasplenic injection of the tumor cells [17]. Such contrasting results are probably explained by the presence or absence of IL-12 responsive cells at the tumor site. C26 tumors growing s.c. are characterized by a
The TSA mammary carcinoma model
The TSA cell line was recently derived from a spontaneous mouse mammary carcinoma [24]. During the last 5 years, the TSA cell line has been widely distributed to several laboratories and, unlike other cell lines that have been established long time ago, it offers the opportunity of comparison among different studies largely avoiding the problem of cell variants. The TSA cells have been genetically engineered to release several cytokines: IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, GM-CSF,
The SCK mammary carcinoma and K1735 melanoma models
In many murine tumor models, enhanced host rejection of tumor cells has been accomplished by engineering cells to express B7 co-stimulatory molecules or creating an environment rich in certain cytokines. In both human and mouse T cells, B7/anti-CD28 stimulation and IL-12 have been demonstrated to induce a strong synergistic stimulation, including IFN-γ production and proliferation [28], [29]. Strikingly, strong cytokine production and proliferation was induced by anti-CD28 and IL-12 stimulation
Inhibition of angiogenesis plays an important role in the anti-tumor effect of IL-12
IL-12 treatment was shown to almost completely inhibit corneal neo-vascularization in C57BL/6, SCID, and beige mice [41]. This potent suppression of angiogenesis was prevented by the administration of IFN-γ-neutralizing antibodies, suggesting that the suppression was mediated through IFN-γ. In addition, the administration of IFN-γ reproduced the anti-angiogenic effects observed during treatment with IL-12 [41]. Thus, IL-12 strongly inhibits neo-vascularization and this effect is not mediated by
IL-12 effects in models of spontaneous or chemically induced carcinogenesis
The ability of IL-12 to prevent tumors when administered to mice with a genetic risk of cancer was studied in two lines of transgenic mice expressing the rat HER-2/neu oncogene under the transcriptional control of mouse mammary tumor virus (MMTV). In both lines, treatment with IL-12 delayed mammary tumor onset and reduced tumor multiplicity [60]. IL-12 was particularly effective in inhibiting the progress from mammary hyperplasia to carcinoma characterized by active neo-angiogenesis with
Natural inducers of IL-12
The inherent toxicity of IL-12 given systemically could be attenuated using compounds able to induce IL-12 production physiologically. At least two compounds that have been widely investigated are worth reporting.
The glycolipid α-galactosylceramide (α-GalCer) originally isolated from marine sponge, is a specific ligand for an invariant antigen T-cell receptor encoded by the Va14 and Ja281 gene segments that are constitutively expressed by NKT cells [67] This unique T-cell population is
IL-12 clinical trials in cancer patients
Although the results from pre-clinical experimental models of cancer immunotherapy have generated much interest in the possibility to use IL-12 as an anti-tumor agent in the clinic, reported clinical trials until now have been limited and IL-12 has shown to have only a modest clinical efficacy joined to a considerable toxicity. However, the results of the clinical trials, and the knowledge derived from the pre-clinical experimentation suggest that optimal protocols may not have been used in the
Conclusions
IL-12 plays important roles in vivo in the regulation of inflammatory responses, innate resistance to infection, and adaptive immunity. It is required for efficient resistance to many pathogens, particularly bacteria and intracellular parasites against which the Th1 responses induced by IL-12 are very effective [1]. Patients with genetic deficiencies in the expression of IL-12 p40 chain or the IL-12Rβ1 chain are susceptible to bacterial infections, particularly by Mycobacterium and Salmonella
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