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. 1995 Oct 10;92(21):9791–9795. doi: 10.1073/pnas.92.21.9791

Antibody-targeted superantigens are potent inducers of tumor-infiltrating T lymphocytes in vivo.

M Dohlsten 1, J Hansson 1, L Ohlsson 1, M Litton 1, T Kalland 1
PMCID: PMC40888  PMID: 7568219

Abstract

Recruitment of antigen-specific tumor-infiltrating lymphocytes (TILs) is a major goal for immunotherapy of malignant tumours. We now describe that T-cell-activating superantigens targeted to a tumor by monoclonal antibodies induced large numbers of pseudospecific TILs and eradication of micrometastases. As a model for tumor micrometastases, syngeneic B16 melanoma cells transfected with the human colon carcinoma antigen C215 were injected intravenously into C57BL/6 mice and therapy with an anti-C215 Fab fragment-staphylococcal enterotoxin A (C215Fab-SEA) fusion protein reacting with the C215 antigen was initiated when visible lung metastases were established. More than 90% reduction of the number of lung metastases was observed when mice carrying 5-day-old established lung metastases were treated with C215Fab-SEA. The antitumor effect of C215Fab-SEA was shown to be T-cell-dependent since no therapeutic effect was seen in T-cell-deficient nude mice. Depletion of T-cell subsets by injection of monoclonal antibody demonstrated that CD8+ cells were the most prominent effector cells although some contribution from CD4+ cells was also noted. C215Fab-SEA treatment induced massive tumor infiltration of CD4+ and CD8+ T cells, while only scattered T cells were observed in untreated tumors. SEA treatment alone induced a slight general inflammatory response in the lung parenchyme, but no specific accumulation of T cells was seen in the tumor. TILs induced by C215Fab-SEA were mainly CD8+ but a substantial number of CD4+ cells were also present. Immunohistochemical analysis showed strong production of the tumoricidal cytokines tumor necrosis factor alpha and interferon gamma in the tumor. Thus, the C215Fab-SEA fusion protein targets effector T lymphocytes to established tumors in vivo and provokes a strong local antitumor immune response.

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Selected References

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  1. Baskar S., Glimcher L., Nabavi N., Jones R. T., Ostrand-Rosenberg S. Major histocompatibility complex class II+B7-1+ tumor cells are potent vaccines for stimulating tumor rejection in tumor-bearing mice. J Exp Med. 1995 Feb 1;181(2):619–629. doi: 10.1084/jem.181.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Björk P., Jönsson U., Svedberg H., Larsson K., Lind P., Dillner J., Hedlund G., Dohlsten M., Kalland T. Isolation, partial characterization, and molecular cloning of a human colon adenocarcinoma cell-surface glycoprotein recognized by the C215 mouse monoclonal antibody. J Biol Chem. 1993 Nov 15;268(32):24232–24241. [PubMed] [Google Scholar]
  3. Brodin N. T., Jansson B., Hedlund G., Sjögren H. O. Use of a monoclonal rat anti-mouse Ig light chain (RAMOL-1) antibody reduces background binding in immunohistochemical and fluorescent antibody analysis. J Histochem Cytochem. 1989 Jul;37(7):1013–1024. doi: 10.1177/37.7.2499618. [DOI] [PubMed] [Google Scholar]
  4. Cameron R. B., Spiess P. J., Rosenberg S. A. Synergistic antitumor activity of tumor-infiltrating lymphocytes, interleukin 2, and local tumor irradiation. Studies on the mechanism of action. J Exp Med. 1990 Jan 1;171(1):249–263. doi: 10.1084/jem.171.1.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen L., McGowan P., Ashe S., Johnston J., Li Y., Hellström I., Hellström K. E. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J Exp Med. 1994 Feb 1;179(2):523–532. doi: 10.1084/jem.179.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dohlsten M., Abrahmsén L., Björk P., Lando P. A., Hedlund G., Forsberg G., Brodin T., Gascoigne N. R., Förberg C., Lind P. Monoclonal antibody-superantigen fusion proteins: tumor-specific agents for T-cell-based tumor therapy. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8945–8949. doi: 10.1073/pnas.91.19.8945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dohlsten M., Björklund M., Sundstedt A., Hedlund G., Samson D., Kalland T. Immunopharmacology of the superantigen staphylococcal enterotoxin A in T-cell receptor V beta 3 transgenic mice. Immunology. 1993 Aug;79(4):520–527. [PMC free article] [PubMed] [Google Scholar]
  8. Hedlund G., Dohlsten M., Petersson C., Kalland T. Superantigen-based tumor therapy: in vivo activation of cytotoxic T cells. Cancer Immunol Immunother. 1993;36(2):89–93. doi: 10.1007/BF01754407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Johnson H. M., Russell J. K., Pontzer C. H. Staphylococcal enterotoxin microbial superantigens. FASEB J. 1991 Sep;5(12):2706–2712. doi: 10.1096/fasebj.5.12.1916093. [DOI] [PubMed] [Google Scholar]
  10. Kalland T., Hedlund G., Dohlsten M., Lando P. A. Staphylococcal enterotoxin-dependent cell-mediated cytotoxicity. Curr Top Microbiol Immunol. 1991;174:81–92. doi: 10.1007/978-3-642-50998-8_6. [DOI] [PubMed] [Google Scholar]
  11. Li Y., McGowan P., Hellström I., Hellström K. E., Chen L. Costimulation of tumor-reactive CD4+ and CD8+ T lymphocytes by B7, a natural ligand for CD28, can be used to treat established mouse melanoma. J Immunol. 1994 Jul 1;153(1):421–428. [PubMed] [Google Scholar]
  12. Mareel M., Dragonetti C., Tavernier J., Fiers W. Tumor-selective cytotoxic effects of murine tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) in organ culture of B16 melanoma cells and heart tissue. Int J Cancer. 1988 Sep 15;42(3):470–473. doi: 10.1002/ijc.2910420327. [DOI] [PubMed] [Google Scholar]
  13. Marincola F. M., Ettinghausen S., Cohen P. A., Cheshire L. B., Restifo N. P., Mulé J. J., Rosenberg S. A. Treatment of established lung metastases with tumor-infiltrating lymphocytes derived from a poorly immunogenic tumor engineered to secrete human TNF-alpha. J Immunol. 1994 Apr 1;152(7):3500–3513. [PMC free article] [PubMed] [Google Scholar]
  14. Scherer M. T., Ignatowicz L., Winslow G. M., Kappler J. W., Marrack P. Superantigens: bacterial and viral proteins that manipulate the immune system. Annu Rev Cell Biol. 1993;9:101–128. doi: 10.1146/annurev.cb.09.110193.000533. [DOI] [PubMed] [Google Scholar]
  15. Sundstedt A., Dohlsten M., Hedlund G., Höidén I., Björklund M., Kalland T. Superantigens anergize cytokine production but not cytotoxicity in vivo. Immunology. 1994 May;82(1):117–125. [PMC free article] [PubMed] [Google Scholar]
  16. Townsend S. E., Allison J. P. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science. 1993 Jan 15;259(5093):368–370. doi: 10.1126/science.7678351. [DOI] [PubMed] [Google Scholar]

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