The Journal of Experimental Medicine
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Published 11 February 2002. doi:10.1084/jem.20010032
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© Rockefeller University Press, 0022-1007/2002/2/423/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 4, February 18, 2002 423-435

Original Article

 Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance

Linh T. Nguyen1, Alisha R. Elford1, Kiichi Murakami1, Kristine M. Garza2, Stephen P. Schoenberger3, Bernhard Odermatt4, Daniel E. Speiser5 and Pamela S. Ohashi1

1 Departments of Immunology and Medical Biophysics, Ontario Cancer Institute, Toronto, ON M5G 2M9 Canada
2 Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968
3 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
4 Institute of Pathology, Department of Experimental Pathology, University Hospital, 8091 Zurich, Switzerland
5 Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, CHUV, CH-1005 Lausanne, Switzerland

Address correspondence to Pamela S. Ohashi, Ontario Cancer Institute, 610 University Ave., 8-327 Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2000 ext. 5470; Fax: 416-946-2086; E-mail: pohashi{at}uhnres.utoronto.ca

Using a tumor model of spontaneously arising insulinomas expressing a defined tumor-associated antigen, we investigated whether tumor growth promotes cross-presentation and tolerance of tumor-specific T cells. We found that an advanced tumor burden enhanced cross-presentation of tumor-associated antigens to high avidity tumor-specific T cells, inducing T cell proliferation and limited effector function in vivo. However, contrary to other models, tumor-specific T cells were not tolerized despite a high tumor burden. In fact, in tumor-bearing mice, persistence and responsiveness of adoptively transferred tumor-specific T cells were enhanced. Accordingly, a potent T cell–mediated antitumor response could be elicited by intravenous administration of tumor-derived peptide and agonistic anti-CD40 antibody or viral immunization and reimmunization. Thus, in this model, tumor growth promotes activation of high avidity tumor-specific T cells instead of tolerance. Therefore, the host remains responsive to T cell immunotherapy.

Key Words: neoplasms • immunotherapy • cytotoxic T lymphocytes • immune tolerance • CD40


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