The Journal of Experimental Medicine
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Published online 13 December 2004 doi:10.1084/jem.20041240
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1581-1592
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Reciprocal Changes in Tumor Antigenicity and Antigen-specific T Cell Function during Tumor Progression

Gang Zhou1, Zhengbin Lu2, John D. McCadden1, Hyam I. Levitsky1, and Aimee L. Marson1

1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231
2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213

Address correspondence to Hyam I. Levitsky, Dept. of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Ste. 4M51, Baltimore, MD 21231. Phone: (410) 614-0552; Fax: (410) 614-9705; email: hy{at}jhmi.edu

Two seemingly incompatible models exist to explain the progression of cancers in immunocompetent hosts. The cancer immunosurveillance hypothesis posits that recognition of transformed cells by the immune system results in the generation of an effector response that may impede tumor growth. Clinically detectable cancer results from the emergence of tumor variants that escape this selective pressure. Alternatively, induction of immune tolerance to tumor antigens may enable cancer progression. We established a model where changes in the function of tumor-specific T cells and in tumor antigen expression could be followed during cancer progression. Early recognition of antigen led to activation, expansion, and effector function in tumor-specific CD4+ T cells resulting in the outgrowth of tumors expressing substantially reduced levels of antigen. Antigen loss was not complete, however, and levels remained above the threshold required for tumor-specific T cell recognition in vivo. In the face of persisting antigen, T cell tolerance ensued, leading to an impaired ability to mediate further antigen loss. Together, these studies establish that the processes of immunosurveillance and tumor editing coexist with a process in which the functional tumor-specific T cell repertoire is also "edited," reconciling two hypotheses historically central to our attempts to understand host antitumor immunity.

Key Words: immunosurveillance • immunoediting • immune tolerance • T lymphocyte • tumor escape

Abbreviations used in this paper: BrdU, bromodeoxyuridine; CFSE, 5,6-carboxy-fluorescein succinimidyl ester; HA, haemaglutinin; qRT-PCR, quantitative real-time RT-PCR.


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