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Herpes Simplex Virus (HSV)-Mediated ICAM-1 Gene Transfer Abrogates Tumorigenicity and Induces Anti-Tumor Immunity

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Abstract

Background

Costimulatory and cellular adhesion molecules are thought to be essential components of antigen presentation in the immune response to cancer. The current studies examine gene transfer utilizing herpes viral amplicon vectors (HSV) to direct surface expression of adhesion molecules, and specifically evaluate the potential of a tumor-expressing intercellular adhesion molecule-1 (ICAM-1) to elicit an anti-tumor response.

Materials and Methods

The human ICAM-1 (hICAMI) gene was inserted into an HSV amplicon vector and tested in a transplantable rat hepatocellular carcinoma and in a human colorectal cancer cell line. Cell surface ICAM-1 expression was assessed by flow cytometry. Lymphocyte binding to HSV-hICAM1-transduced cells was compared with that to cells transduced with HSV not carrying the ICAM gene. Tumorigenicity of HSV-hICAM1-transduced tumor cells were tested in syngeneic Buffalo rats. Additionally, immunization with irradiated (10,000 rads) HSV-hICAM1-transduced tumor cells was performed to determine its effect on tumor growth.

Results

A 20-min exposure of tumor cells at a multiplicity of infection (MOI) of 1 resulted in high-level cell surface expression of human ICAM in approximately 25% of tumor cells. Transduced rat or human tumor cells exhibited significantly enhanced binding of lymphocytes (p < 0.05). HSV-hICAM1-transduced cells elicited an increase in infiltration by CD4+ lymphocytes in vivo and exhibited decreased tumorigenicity. Immunization with irradiated HSV-hICAM1-transduced cells protected against growth of subsequent injected parental tumor cells.

Conclusions

HSV amplicon-mediated gene transfer is an efficient method for modifying the cell surface expression of adhesion molecules. Increased tumor expression of ICAM-1 represents a promising immune anti-cancer strategy.

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References

  1. Dustin ML, Springer TA. (1991) Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Annu. Rev. Immunol 9: 27–66.

    Article  CAS  PubMed  Google Scholar 

  2. Rothlein R, Dustin ML, Marlin SD, Springer TA. (1986) A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J. Immunol. 137: 1270–1274.

    PubMed  CAS  Google Scholar 

  3. Springer TA. (1990) Adhesion receptors of the immune system. Nature 346: 425–434.

    Article  CAS  PubMed  Google Scholar 

  4. Voraberger G, Schafer R, Stratowa C. (1991) Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5′-regulatory region: Induction by cytokines and phorbol ester. J. Immunol. 147: 2777–2786.

    PubMed  CAS  Google Scholar 

  5. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA. (1986) Induction by IL 1 and inter-feron-gamma: Tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J. Immunol. 137: 245–254.

    PubMed  CAS  Google Scholar 

  6. Katsumoto Y, Monden T, Takeda T, et al. (1996) Analysis of cytotoxic activity of the CD4 positive T lymphocytes generated by local immunotherapy. Br. J. Cancer 73: 110–116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fady C, Gardner A, Gera JF, Lichtenstein A. (1993) Interferon-gamma-induced increased sensitivity of HER2/neu-overexpressing tumor cells to lymphokine-activated killer cell lysis: Importance of ICAM-1 in binding and post-binding events. Cancer Immunol. Immunother. 37: 329–336.

    Article  CAS  PubMed  Google Scholar 

  8. Boyer MW, Orchard PJ, Gorden KB, Anderson PM, Mclvor RS, Blazar BR. (1995) Dependency on intercellular adhesion molecule recognition and local interleukin-2 provision in generation of a in vivo CD8 positive T-cell immune response to murine myeloid leukemia. Blood 85: 2498–2506.

    PubMed  CAS  Google Scholar 

  9. Makgoba MW, Sanders ME, Ginther Luce GE, et al. (1988) Functional evidence that intercellular adhesion molecule-1 (ICAM-1) is a ligand for LFA-1-dependent adhesion in T cell-mediated cytotoxicity. Eur. J. Immunol. 18: 637–640.

    Article  CAS  PubMed  Google Scholar 

  10. Altmann DM, Hogg N, Trowsdale J, Wilkinson D. (1989) Cotransfection of ICAM-1 and HLA-DR reconstitutes human antigen-presenting cell function in mouse L cells. Nature 338: 512–514.

    Article  CAS  PubMed  Google Scholar 

  11. Vanky F, Wang P, Patarroyo M, Klein E. (1990) Expression of the adhesion molecule ICAM-1 and major histocompatibility complex class I antigens on human tumor cells is required for their interaction with autologous lymphocytes in vitro. Cancer Immunol. Immunother. 31: 19–27.

    Article  CAS  PubMed  Google Scholar 

  12. Gregory CD, Murray RJ, Edwards CF, Rickinson AB. (1988) Downregulation of cell adhesion molecules LFA-3 and ICAM-1 in Epstein-Barr virus-positive Burkitt’s lymphoma underlies tumor cell escape from virus-specific T cell surveillance. J. Exp. Med. 167: 1811–1824.

    Article  CAS  PubMed  Google Scholar 

  13. Dustin ML, Staunton DE, Springer TA. (1988) Supergene families meet in the immune system. Immunol. Today 9: 213–215.

    Article  CAS  PubMed  Google Scholar 

  14. Sartor WM, Kyprianou N, Fabian DF, Lefor AT. (1995) Enhanced expression of ICAM-1 in a murine fibrosarcoma reduces tumor growth rate. J. Surg. Res. 59: 66–74.

    Article  CAS  PubMed  Google Scholar 

  15. Wei K, Wilson JG, Jurgensen CH, Iannone MA, Wolberg G, Huber BE. (1996) Xenogeneic ICAM-1 gene transfer suppresses tumorigenicity and generates protective antitumor immunity. Gene Ther. 3: 531–541.

    PubMed  CAS  Google Scholar 

  16. Herrlinger U, Kramm CM, Aboody-Guterman KS, et al. (1988) Pre-existing herpes simplex virus 1 (HSV-1) immunity decreases, but does not abolish, gene transfer to experimental brain tumors by a HSV-1 vector. Gene Ther. 5: 809–819.

    Article  CAS  Google Scholar 

  17. Kramm CM, Chase M, Herrlinger U, et al. (1997) Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy. Hum. Gene Ther. 8: 2057–2068.

    Article  CAS  PubMed  Google Scholar 

  18. Geller AI, Keyomarsi K, Bryan J, Pardee AB. (1990) An efficient deletion mutant packaging system for defective herpes simplex virus vectors: Potential applications to human gene therapy and neuronal physiology. Troc. Nat. Acad. Sci. U.S.A. 87: 8950–8954.

    Article  CAS  Google Scholar 

  19. Fong YF, Federoff HJ, Brownlee M, Blumberg D, Blumgart LH, Brennan MF. (1995) Rapid and efficient gene transfer in human hepatocytes by herpes viral vectors. Hepatology 22: 723–729.

    PubMed  CAS  Google Scholar 

  20. Geller AI, Federoff H. (1991) The use of HSV-1 vectors to introduce heterologous genes into neurons: Implications for gene therapy. In: Cohen-Haguenauer M, Boiron M (eds). Human Gene Transfer. John Libbey Eurotext, Paris, pp. 63–73.

    Google Scholar 

  21. Karpoff H, D’Angelica M, Blair S, Brownlee MD, Federoff H. (1997) Prevention of hepatic tumor metastases in rats with herpes viral vaccines and gamma-interferon. J. Clin. Invest. 99: 799–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tung C, Federoff HJ, Brownlee M, Karpoff H, Weigel T, Brennan MF, Fong Y. (1996) Rapid production of interleukin-2-secreting tumor cells by herpes simplex virus-mediated gene transfer: Implications for autologous vaccine production. Hum. Gene Ther. 7: 2217–2224.

    Article  CAS  PubMed  Google Scholar 

  23. Miki I, Ishihara N, Otoshi M, Kase H. (1993) Simple colorimetric cell-cell adhesion assay using MTT-stained leukemia cells. J. Immunol. Methods 164: 255–261.

    Article  CAS  PubMed  Google Scholar 

  24. Kanof ME, Smith PD, Zola H. (1996) Preparation of human mononuclear cell populations and sub-populations. In: Coligan JE, Kruisbeek AM, Margulies DH, Shevah EM, Strober W. (eds). Current Protocols in Immunology. John Wiley & Sons, New York, p. 7.1.1–7.1.7.

    Google Scholar 

  25. Herberman RB. (1989) Interleukin-2 therapy of human cancer: Potential benefits versus toxicity. J. Clin. Oncol. 7: 1–4.

    Article  CAS  PubMed  Google Scholar 

  26. Lee RL, Lotze MT, Skibber JM, et al. (1989) Cardiorespiratory effects of immunotherapy with interleukin-2. J. Clin. Oncol. 7: 7–20.

    Article  CAS  PubMed  Google Scholar 

  27. Iwanuma Y, Kato K, Yagita H, Okumura K. (1995) Induction of tumor-specific cytotoxic T lymphocytes and natural killer cells by tumor cells transfected with the interleukin-2 gene. Cancer Immunol. Immunother. 40: 17–23.

    Article  CAS  PubMed  Google Scholar 

  28. Ley V, Langlade-Demoyen P, Kourilsky P, Larsson-Sciard E. (1991) Interleukin 2-dependant activation of tumor specific cytotoxic T lymphocytes in vivo. Eur. J. Immunol. 21: 851–854.

    Article  CAS  PubMed  Google Scholar 

  29. 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. U.S.A. 90: 3539–3543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Levitsky H, Lazenby A, Hayashi RJ, Pardoll DM. (1994) In vivo priming of two distinct antitumor effector populations: The role of MHC class I expression. J. Exp. Med. 179: 1215–1224.

    Article  CAS  PubMed  Google Scholar 

  31. Golumbek P, Lazenby A, Levitsky HI, et al. (1991) Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science 254: 713–716.

    Article  CAS  PubMed  Google Scholar 

  32. Porgador A, Tzehoval E, Katz A, et al. (1992) Interleukin 6 gene transfection into Lewis lung carcinoma tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. Cancer Res. 52: 3679–3686.

    PubMed  CAS  Google Scholar 

  33. Eisenthal A, Skornick Y, Merimsky O, et al. (1993) Effect of allogeneic tumor cells, interleukin-2 and interleukin-6, on the growth of subcutaneous syngeneic tumors. Cancer Immunol. Immunother. 37: 233–239.

    Article  CAS  PubMed  Google Scholar 

  34. Connor J, Bannerji R, Saito S, Heston W, Fair W, Gilboa E. (1993) Regression of bladder tumors in mice treated with interleukin 2 gene modified tumor cells. J. Exp. Med. 177: 1127–1134.

    Article  CAS  PubMed  Google Scholar 

  35. Allione A, Consalvo M, Nanni P, et al. (1994) Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants. Cancer Res. 54: 6022–6026.

    PubMed  CAS  Google Scholar 

  36. Fearon ER, Pardoll DM, Itaya T, et al. (1990) Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 60: 397–403.

    Article  CAS  PubMed  Google Scholar 

  37. Hock H, Dorsch M, Kunzendorf U, Qin Z, Diamantstein T, Blankenstein T. (1993) Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma. Proc. Natl. Acad. Sci. U.S.A. 90: 2774–2778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Townsend SE, Allison JP. (1993) Tumor rejection after direct costimulation of CD8 positive cells by B7-transfected melanoma cells. Science 259: 368–370.

    Article  CAS  PubMed  Google Scholar 

  39. Baskar B, Ostrand-Rosenberg S, Nabavi N, Nadler LM, Freeman GJ, Glimcher LH. (1993) Constitutive expression of B7 restores immunogenicity of tumor cells expressing truncated major histocompatibility complex class II molecules. Proc. Natl. Acad. Sci. U.S.A. 90: 5687–5690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen L, Ashe S, Brady WA, (1992) Costimulationv of antitumor immunity by the B7 conterrecptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71: 1093–1102.

    Article  CAS  PubMed  Google Scholar 

  41. Roth JA, Cristiano RJ. (1997) Gene therapy for cancer: What have we done and where are we going? J. Natl. Cancer Inst. 89: 21–39.

    Article  CAS  PubMed  Google Scholar 

  42. Johnson JP. (1991) The role of ICAM-1 in tumor development [review]. Chem. Immunol 50: 143–163.

    Article  CAS  PubMed  Google Scholar 

  43. Becker JC, Drummer R, Hartmann AA, Burg G, Schmidt RE. (1991) Shedding of ICAM-1 from human melanoma cell lines induced by IFN-γ and tumor necrosis factor-α. J. Immunol. 147: 4398–4401.

    PubMed  CAS  Google Scholar 

  44. Simmons DL. (1995) The role of ICAM expression in immunity and disease [review]. Cancer Surv. 24: 141–155.

    PubMed  CAS  Google Scholar 

  45. Koyama S. (1994) Immunosuppressive effect of shedding intercellular adhesion molecule 1 antigen on cell-mediated cytotoxicity against tumor cells. Jpn. J. Cancer Res. 85: 131–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Webb DS, Mostowski HS, Gerrard TL. (1991) Cytokine-induced enhancement of ICAM-1 expression results in increased vulnerability of tumor cells to monocyte-mediated lysis. J. Immunol. 146: 3682–3686.

    PubMed  CAS  Google Scholar 

  47. Uzendoski K, Kantor JA, Abrams SI, Schlom J, Hodge JW. (1997) Construction and characterization of a recombinant vaccinia virus expressing murine intercellular adhesion molecule-1: Induction and potnetiation of anti-tumor responses. Hum. Gene Ther. 8: 851–860.

    Article  CAS  PubMed  Google Scholar 

  48. Lu B, Gupta S, Federoff H. (1995) Ex vivo hepatic gene transfer in mouse using a defective herpes simplex virus-1 vector. Hepatology 21: 752–759.

    PubMed  CAS  Google Scholar 

  49. Lotze MT, Chang AE, Seipp CA, Simpson C, Vetto JT, Rosenberg SA. (1986) High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. JAMA 256: 3117–3124.

    Article  CAS  PubMed  Google Scholar 

  50. Rosenberg SA, Lotze MT, Muul LM, et al. (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 316: 889–897.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by grants CA76416 and CA72632 from the National Institutes of Health and from the Sara Chait Foundation.

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Authors and Affiliations

  1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10021, USA

    Michael D’Angelica, Cindy Tung, Peter Allen, Keith Delman, Thomas Delohery &  Yuman Fong

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    David Klimstra

  3. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

    Michael Brownlee

  4. Department of Neurology, Medicine, Microbiology and Immunology, University of Rochester, Rochester, New York, USA

    Marc Halterman & Howard Federoff

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  1. Michael D’Angelica
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Correspondence to Yuman Fong.

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D’Angelica, M., Tung, C., Allen, P. et al. Herpes Simplex Virus (HSV)-Mediated ICAM-1 Gene Transfer Abrogates Tumorigenicity and Induces Anti-Tumor Immunity. Mol Med 5, 606–616 (1999). https://doi.org/10.1007/BF03402073

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