Nature Medicine
5, 677 - 685 (1999)
doi:10.1038/9525
Characterization of circulating T cells specific for tumor-associated
antigens in melanoma patientsPeter P. Lee1, Cassian Yee2, Peter A. Savage1, Lawrence Fong3, Dirk Brockstedt3, Jeffrey S. Weber7, Denise Johnson4, Susan Swetter5, John Thompson2, Philip D. Greenberg2, Mario Roederer6
& Mark M. Davis11
Howard Hughes Medical Institute/Department of Microbiology
and Immunology, Stanford University, Stanford, California
94305, USA
3
Blood Center, Stanford University, Stanford
, California 94305, USA
4
Department of Surgery/Division of Surgical Oncology,
Stanford University, Stanford, California
94305, USA
6
Department of Genetics, Stanford University,
Stanford, California 94305, USA
5
Department of Dermatology, Stanford University
and Palo Alto Veterans Administration Hospital, 2
Department of Medicine, University of Washington
and Fred Hutchinson Cancer Research Center, Seattle,
Washington 98109, USA
7
USC Norris Cancer Center, Los Angeles,
California 90033, USA
8
P.P.L and C.Y. contributed equally to this study
Correspondence should be addressed to Mark M. Davis mdavis@cmgm.stanford.eduWe identified circulating CD8+ T-cell populations specific
for the tumor-associated antigens (TAAs) MART-1 (27-35) or tyrosinase (368-376)
in six of eleven patients with metastatic melanoma using peptide/HLA-A*0201
tetramers. These TAA-specific populations were of two phenotypically distinct
types: one, typical for memory/effector T cells; the other, a previously undescribed
phenotype expressing both naive and effector cell markers. This latter type
represented more than 2% of the total CD8+ T cells in one patient,
permitting detailed phenotypic and functional analysis. Although these cells
have many of the hallmarks of effector T cells, they were functionally unresponsive,
unable to directly lyse melanoma target cells or produce cytokines in response
to mitogens. In contrast, CD8+ T cells from the same patient
were able to lyse EBV-pulsed target cells and showed robust allogeneic responses.
Thus, the clonally expanded TAA-specific population seems to have been selectively
rendered anergic in vivo. Peptide stimulation of the TAA-specific T-cell
populations in other patients failed to induce substantial upregulation of
CD69 expression, indicating that these cells may also have functional defects,
leading to blunted activation responses. These data demonstrate that systemic
TAA-specific T-cell responses can develop de novo in cancer patients,
but that antigen-specific unresponsiveness may explain why such cells are
unable to control tumor growth.
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