Induction and maintenance of cytotoxic T lymphocyte (CTL) activity specific for a primary endogenous tumor was investigated in vivo. The simian virus 40 T antigen (Tag) expressed under the control of the rat insulin promoter (RIP) induced pancreatic β-cell tumors producing insulin, causing progressive hypoglycemia. As an endogenous tumor antigen, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) was introduced also under the control of the RIP. No significant spontaneous CTL activation against GP was observed. However, LCMV infection induced an antitumor CTL response which efficiently reduced the tumor mass, resulting in temporarily normalized blood glucose levels and prolonged survival of double transgenic RIP(GP × Tag2) mice (137 ± 18 d) as opposed to control RIP-Tag2 mice (88 ± 8 d). Surprisingly, the tumor-specific CTL response was not sustained despite the facts that the tumor cells continued to express MHC class I and LCMV-GP–specific CTLs were present and not tolerized. Subsequent adoptive transfer of virus activated spleen cells into RIP(GP × Tag2) mice further prolonged survival (168 ± 11 d), demonstrating continued expression of the LCMV-GP tumor antigen and MHC class I. The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo. Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy. In addition, the data suggest that the risk for induction of chronic autoimmune diseases is limited, which may encourage immunotherapy against antigens selectively but not exclusively expressed by the tumor.
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29 August 1997
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August 29 1997
Self Antigens Expressed by Solid Tumors Do Not Efficiently Stimulate Naive or Activated T Cells: Implications for Immunotherapy
Daniel E. Speiser,
Daniel E. Speiser
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Renata Miranda,
Renata Miranda
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Arsen Zakarian,
Arsen Zakarian
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Martin F. Bachmann,
Martin F. Bachmann
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Kim McKall-Faienza,
Kim McKall-Faienza
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Bernhard Odermatt,
Bernhard Odermatt
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Douglas Hanahan,
Douglas Hanahan
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Rolf M. Zinkernagel,
Rolf M. Zinkernagel
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Pamela S. Ohashi
Pamela S. Ohashi
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
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Daniel E. Speiser
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Renata Miranda
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Arsen Zakarian
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Martin F. Bachmann
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Kim McKall-Faienza
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Bernhard Odermatt
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Douglas Hanahan
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Rolf M. Zinkernagel
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Pamela S. Ohashi
From the *Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada; ‡Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0534; and §Institute for Experimental Immunology, University Hospital of Zürich, CH-8091 Zürich, Switzerland
Address correspondence to Daniel E. Speiser, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: 416-946-4501, extension 5470. FAX: 416-946-2086.
1
Abbreviations used in this paper: GP, glycoprotein; LCMV, lymphocytic choriomeningitis virus; RIP, rat insulin promoter; Tag, T antigen.
Received:
February 18 1997
Revision Received:
June 25 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (5): 645–653.
Article history
Received:
February 18 1997
Revision Received:
June 25 1997
Citation
Daniel E. Speiser, Renata Miranda, Arsen Zakarian, Martin F. Bachmann, Kim McKall-Faienza, Bernhard Odermatt, Douglas Hanahan, Rolf M. Zinkernagel, Pamela S. Ohashi; Self Antigens Expressed by Solid Tumors Do Not Efficiently Stimulate Naive or Activated T Cells: Implications for Immunotherapy . J Exp Med 29 August 1997; 186 (5): 645–653. doi: https://doi.org/10.1084/jem.186.5.645
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