Abstract
Interleukin 12 (IL-12) is a disulfide-linked heterodimer molecule produced predominantly by professional antigen presenting cells. It promotes the induction of sundry biological effects with significant relevance to antitumor immunity, such as enhancing a T H 1 helper response, an in vivo antiangiogenic effect, induction of adhesion molecules that assist in lymphocyte homing to sites of tumor growth, and a direct stimulatory effect on both T-cells and NK cells. We tested the efficacy of an antimetastatic vaccine composed of autologous murine D122 cells transfected with both subunits of IL-12 cDNA to express biologically-active IL-12 molecule. Expression of IL-12 by D122 cells significantly reduced their tumorigenicity and metastatic potential in immunocompetent syngeneic hosts. Furthermore, vaccination of mice with 2 × 106 irradiated IL-12-transfected D122 cells engendered a protective CTL response which rejected a subsequent challenge with parental D122 cells and eradicated lung micrometastasis in animals whose primary tumors have been surgically removed. The antitumor effects of IL-12 were mediated primarily by its ability to induce gIFN expression in vivo. CD8 + T-cells as well as NK cells were crucial in the execution of the antitumor effects of IL-12. These results suggest that autologous tumor cells expressing IL-12 by gene transfer are a potent antitumor vaccine able to induce a systemic immune response against poorly immunogenic and spontaneously metastatic tumors. ©Lippincott Williams & Wilkins
Similar content being viewed by others
References
Dranoff G, Jaffee E, Lazenby A, et al.,1993, Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA,90, 3539-43.
Colombo MP and Rodolfo M, 1995, Tumor cells enginnered to produce cytokines or cofactors as cellular vaccines: do animal studies really support clinical trials ? Cancer Immunol Immunother, 41, 265-70.
Schoenhaut DS, Chua AO, Wolitzky AG, et al.,1992, Cloning and expression of murine Il-12. J Immunol,148, 3433-40.
Banks, RE, Patel, PM and Selby PJ, 1995, Interleukin 12: a new clinical player in cytokine therapy. Br J Cancer, 71, 655-9.
Tahara H Lotze MT, 1995, Antitumor effects of interleukin 12 (IL-12): applications in the immunotherapy and gene therapy of cancer. Gene Therapy, 2, 96-106.
Romagnani S, 1995, Biology of human TH1 and TH2 cells. Clinical Immunol, 15, 121-9.
Trinchieri G, 1993, Interleukin 12 and its role in the generation of TH1 cells. Immunol Today, 14, 335-338.
Voest EE, Kenyon BM, O'Reilly MS, et al.,1995, Inhibition of angiogenesis in vivoby interleukin 12. J Natl Cancer Inst, 87, 581-6.
Ogawa M, Tsutsui T, Zou J, et al.,1997, Enhanced induction of very late antigen 4/lymphocyte function-associated antigen 1-dependent T-cell migration to tumor sites following administration of interleukin 12. Cancer Res, 57, 2216-22.
Kim JJ, Ayyavoo V, Bagarazzi ML, et al.,1997, In vivoengineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol, 158, 816-26.
Tahara H, Zeh III HJ, Storkus WJ, et al.,1994, Fibroblasts genetically engineered to secrete interleukin 12 can suppress tumor growth and induce anti-tumor immunity to a murine melanoma in vivo. Cancer Res, 54, 182-9.
Caruso M, Pham-Nguyen K, Kwong Y, et al.,1996, Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. Proc Natl Acad Sci USA,93, 11302-11306.
Porgador A, Bannerji R, Watanabe Y, et al.,1993, Antimetastatic vaccination of tumor-bearing mive with two types of IFN-γ gene-inserted tumor cells. J Immunol, 150, 1458-70.
Gately, MK and Chizzonite, R, 1992, Measurement of human and mouse interleukin-12. In: Coligan, JE, Kruisbeek, AM, Margulies, DH, Shevach, EM and Strober, W., eds. Current Protocols in Immunology,. New York: Green Publishing and Wiley-Interscience, pp. 6.
Porgador A, Tzehoval E, Katz A, et al.,1992, IL-6 gene transfection into 3LL tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. Cancer Res, 52, 3679-86.
Brunda MJ, Luistro L, Warrier RR, et al.,1993, Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med, 178, 1223-30.
Takeda K, Seki S, Ogasawara K, et al.,1996, Liver NK1.1+ CD4+ αβ T cells activated by IL-12 as a major effect in inhibition of experimental tumor metastasis. J Immunol, 156, 3366-73.
Hashimoto W, Takeda K, et al.,1995, Cytotoxic NK 1.1 Ag+ αβ T cells with intermediate TCR induced in the liver of mice by IL-12. J Immunol, 154, 4333-40.
Nastala CL, Edington HD, McKinney TC, et al.,1994, Recombinant IL-12 administration induces tumor regression in association with IFN-γ production. J Immunol, 153, 1697-706.
Martinotti A, Stoppacciaro A, Vagliani M, et al.,1995, CD4 T cells inhibit in vivothe CD8-mediated immune response against murine colon carcinoma cells transduced with interleukin 12 genes. Eur J Immunol, 25, 137-46.
Lamont AG, Adorini L, 1996, IL-12: A key cytokine in immune regulation. Immunol. Today, 17, 214-7.
Pardoll DM, 1995, Paracrine cytokine adjuvants in cancer immunotherapy. Annu Rev Immunol, 13, 399-415.
Cavallo F, Signorelli P, Giovarelli M, et al.,1997, Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. J Natl Cancer Ins, 89, 1049-58.
Rodolfo M, Zilocchi C, Melani C, et al.,1996, Immunotherapy of experimental metastases by vaccination with interleukin gene-transduced adenocarcinoma cells sharing tumor-associated antigens: Comparison between IL-12 and IL-2 gene-transduced tumor cell vaccines. J Immunol, 157, 5536-42.
Schoenhaut DA, Chua A, Wolitzky A, et al.,1992, Cloning and expression of murine IL-12. J Immunol, 148, 3433-40.
D'Andrea A, Rengaraju M, Valliante N, et al.,1992, Production of NKSF (IL-12) by peripheral blood mononuclear cells. J Exp Med, 180, 211-22.
Zitvogel L, Tahara H, Robbins BD, et al.,1995, Cancer immunotherapy of established tumors with IL-12: effective delivery by genetically-engineered fibroblasts. J Immunol, 155, 1393-403.
Porgador A, Tzehoval E, Vadai E, et al.,1995, Combined vaccination with major histocompatibility class I and interleukin 2 gene-transdused melanoma cells synergises the cure of postsurgical established lung metastases. Cancer Res, 55, 4941-9.
Gately MK, Warrier RR, Honasoge S, et al.,1994, Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocytes activity and induces production of IFN-γ in vivo. Int Immunol, 6, 157-67.
Manetti R, Gerosa F, Giudizi MG, et al.,1994, Interleukin 12 induces stable priming for interferon γ (IFN-γ) production during differentiation of human T helper (Th) cells and transient IFN-γ production in established Th2 cell clones, J Exp Med, 179,1273-83.
Seder RA, Gazzinelli R, Sher A and Paul WE, 1993, IL-12 acts directly on CD4+ T cells to enhance priming for IFN-γ production and diminishes IL-4 inhibition of such priming. Proc Natl Acad Sci USA, 90, 10188-93.
Tannebaum CS, Wicker N, Armstrong D, et al.,1996, Cytokine and chemokine expression in tumors of mice recieving systemic therapy with IL-12. J Immunol, 156, 693-9.
Zou J-P, Yamamoto N, Fuji T, et al.,1995, Systemic administration of rIL-12 induces complete tumor regression and protective immunity: Response is correlated with a striking reversal of suppressed IFN-γ production by anti-tumor T cells. Int Immunol, 7,1135-45.
Fallarino F, Uyttenhove C, Boon T and Gajewski TF, 1996, Endogenous IL-12 is necessary for rejection of P815 tumor variants in vivo. J Immunol, 156, 1095-100.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Popovic, D., El-Shami, K.M., Vadai, E. et al. Antimetastatic vaccination against Lewis lung carcinoma with autologous tumor cells modified to express murine Interleukin 12. Clin Exp Metastasis 16, 623–632 (1998). https://doi.org/10.1023/A:1006508413070
Issue Date:
DOI: https://doi.org/10.1023/A:1006508413070