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Immunology |
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital, 1005 Lausanne, Switzerland [D. V., V. D., V. R-G., P. R., J-C. C., D. L.]; University Hospital Benjamin-Franklin, Medizinische Klinik III, Hematology, Oncology and Transfusion Medicine, Free University of Berlin, 12200 Berlin, Germany [C. S., D. N., A. M. A., E. T., U. K.]; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland [D. R., P. G., J-C. C.]; Skin Cancer Unit, German Cancer Research Center, University Hospital Heidelberg, 68135 Mannheim, Germany [D. S.]; Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany [M. L.]; Division of Oncology, Laboratory of Tumor Immunology, University Hospital, 1211 Geneva 14, Switzerland [P-Y. D.]; and Multidisciplinary Oncology Center, University Hospital, 1005 Lausanne, Switzerland [D. L.]
To defend the host from malignancies, the immune system can spontaneouslyraise CD8+ T-cell responses against tumor antigens. Investigatingthe functional state of tumor-reactive cytolytic T cells in cancer patients is a key step for understanding the role of these cells in tumor immunosurveillance and for evaluating the potential of immunotherapeutic approaches of vaccination against cancer. In this study we identified a subset of circulating tumor-reactive CD8+ T lymphocytes, which specifically secreted IFN-
after exposition to autologous tumor cell lines in stage IV metastatic melanoma patients. Additional phenotypic characterization using multicolor flow cytometry revealed that a significant fraction of these cells were CD45RA+CCR7-, a phenotype that has been proposed recently to characterize cytolytic effectors potentially able to home into inflamed tissues. In the case of an HLA-A2-expressing patient, the antigen specificity of this population was identified by using HLA-A2/peptide multimers incorporating a tyrosinase-derived peptide. Consistently with their phenotypic characteristics, A2/tyrosinase peptide multimer+ CD8+ T cells, isolated by cell sorting, were directly lytic ex vivo and able to specifically recognize tyrosinase-expressing tumor cells. Overall, these results provide the first evidence that a proportion of melanoma patients have circulating tumor-reactive T cells, which are lytic effectors cells.
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