Mini Review
Interleukin-12 in anti-tumor immunity and immunotherapy

https://doi.org/10.1016/S1359-6101(01)00032-6Get rights and content

Abstract

Interleukin-12 (IL-12) has an essential role in the interaction between the innate and adaptive arms of immunity by regulating inflammatory responses, innate resistance to infection, and adaptive immunity. Endogenous IL-12 is required for resistance to many pathogens and to transplantable and chemically induced tumors. In experimental tumor models, recombinant IL-12 treatment has a dramatic anti-tumor effect on transplantable tumors, on chemically induced tumors, and in tumors arising spontaneously in genetically modified mice. IL-12 utilizes effector mechanisms of both innate resistance and adaptive immunity to mediate anti-tumor resistance. IFN-γ and a cascade of other secondary and tertiary pro-inflammatory cytokines induced by IL-12 have a direct toxic effect on the tumor cells or may activate potent anti-angiogenic mechanisms. The stimulating activity of IL-12 on antigen-specific immunity relies mostly on its ability to determine or augment Th1 and cytotoxic T lymphocyte responses. Because of this ability, IL-12 has a potent adjuvant activity in cancer and other vaccines. The promising data obtained in the pre-clinical models of anti-tumor immunotherapy have raised much hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity and modest clinical response observed in the clinical trials point to the necessity to plan protocols that minimize toxicity without affecting the anti-tumor effect of IL-12.

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

References (89)

  • X. Ma et al.

    The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells

    J. Exp. Med.

    (1996)
  • M. Kobayashi et al.

    Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes

    J. Exp. Med.

    (1989)
  • S.F. Wolf et al.

    Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells

    J. Immunol.

    (1991)
  • A. D’Andrea et al.

    Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells

    J. Exp. Med.

    (1992)
  • S. Gillessen et al.

    Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist

    Eur. J. Immunol.

    (1995)
  • P. Ling et al.

    Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity

    J. Immunol.

    (1995)
  • G. Carra et al.

    Biosynthesis and posttranslational regulation of human IL-12

    J. Immunol.

    (2000)
  • M.K. Gately et al.

    The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses

    Annu. Rev. Immunol.

    (1998)
  • S.J. Szabo et al.

    Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells

    J. Exp. Med.

    (1997)
  • C.M. Bacon et al.

    Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • M.J. Brunda et al.

    Antitumor and antimetastatic activity of interleukin 12 against murine tumors

    J. Exp. Med.

    (1993)
  • J. Cui et al.

    Requirement for valpha14 NKT cells in IL-12-mediated rejection of tumors

    Science

    (1997)
  • T. Kodama et al.

    Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12

    Eur. J. Immunol.

    (1999)
  • M.J. Smyth et al.

    The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent

    J. Immunol.

    (2000)
  • P. Nanni et al.

    Interleukin 12 gene therapy of MHC-negative murine melanoma metastases

    Cancer Res.

    (1998)
  • C. Chiodoni et al.

    Different requirements for alpha-galactosylceramide and recombinant IL-12 antitumor activity in the treatment of C-26 colon carcinoma hepatic metastases

    Eur. J. Immunol.

    (2001)
  • M. Vagliani et al.

    Interleukin 12 potentiates the curative effect of a vaccine based on interleukin 2-transduced tumor cells

    Cancer Res.

    (1996)
  • A. Martinotti et al.

    CD4 T cells inhibit in vivo CD8-mediated immune response against a murine colon carcinoma transduced with IL-12 genes

    Eur. J. Immunol.

    (1995)
  • K.J. Maloy et al.

    Regulatory T cells in the control of immune pathology

    Nat. Immunol.

    (2001)
  • C. Zilocchi et al.

    Interferon gamma-independent rejection of interleukin 12-transduced carcinoma cells requires CD4+ T cells and granulocyte/macrophage colony-stimulating factor

    J. Exp. Med.

    (1998)
  • M.P. Colombo et al.

    Local cytokine availability elicits tumor rejection and systemic immunity through granulocyte-T-lymphocyte cross-talk

    Cancer Res.

    (1992)
  • M. Rodolfo et al.

    IgG2a induced by interleukin (IL) 12-producing tumor cell vaccines but not IgG1 induced by IL-4 vaccine is associated with the eradication of experimental metastases

    Cancer Res.

    (1998)
  • P. Musiani et al.

    Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha

    Lab. Invest.

    (1996)
  • F. Cavallo et al.

    Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12

    J. Natl. Cancer Inst.

    (1997)
  • E. Di Carlo et al.

    Inhibition of mammary carcinogenesis by systemic interleukin 12 or p185neu DNA vaccination in Her-2/neu transgenic BALB/c mice

    Clin. Cancer Res.

    (2001)
  • M. Kubin et al.

    Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells

    J. Exp. Med.

    (1994)
  • E.E. Murphy et al.

    B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation

    J. Exp. Med.

    (1994)
  • C.M. Coughlin et al.

    B7-1 and interleukin 12 synergistically induce effective antitumor immunity

    Cancer Res.

    (1995)
  • C.M. Coughlin et al.

    The effect of interleukin 12 desensitization on the antitumor efficacy of recombinant interleukin 12

    Cancer Res.

    (1997)
  • L.C. Afonso et al.

    The adjuvant effect of interleukin-12 in a vaccine against Leishmania major

    Science

    (1994)
  • Y. Noguchi et al.

    Influence of interleukin 12 on p53 peptide vaccination against established Meth A sarcoma

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • H. Kurzawa et al.

    Recombinant interleukin 12 enhances cellular immune responses to vaccination only after a period of suppression

    Cancer Res.

    (1998)
  • H.K. Koblish et al.

    Immune suppression by recombinant interleukin (rIL)-12 involves interferon gamma induction of nitric oxide synthase 2 (iNOS) activity: inhibitors of NO generation reveal the extent of rIL-12 vaccine adjuvant effect

    J. Exp. Med.

    (1998)
  • T.K. Tarrant et al.

    Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis

    J. Immunol.

    (1998)
  • Cited by (619)

    View all citing articles on Scopus
    1

    Tel.: +33-4-72-17-27-00; fax: +33-4-78-35-47-50.

    View full text