1. ¹Laboratory of Tumor Immunology, Division of Oncology, Department of Internal Medicine, University Hospital, Geneva, Switzerland
2. ²Department of Clinical Neuroscience and Dermatology, University Hospital, Geneva, Switzerland
3. ³Ludwig Institute for Cancer Research, University Hospital, Lausanne, Switzerland
4. ⁴Genomic Research Laboratory, Division of Infectious Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland

Correspondence: Dr Frédérique-Anne Le Gal, Department of Clinical Neuroscience and Dermatology, 24 rue Micheli du Crest, CH-1211 Geneva 14, Switzerland. E-mail: frederique-anne.legal@hcuge.ch

Received 20 March 2006; Revised 17 July 2006; Accepted 21 August 2006; Published online 12 October 2006.

Abstract

Tumor antigen-specific cytotoxic T cells (CTLs) play a major role in the adaptive immune response to cancers. This CTL response is often insufficient because of functional impairment, tumor escape mechanisms, or inhibitory tumor microenvironment. However, little is known about the fate of given tumor-specific CTL clones in cancer patients. Studies in patients with favorable outcomes may be very informative. In this longitudinal study, we tracked, quantified, and characterized functionally defined antigen-specific T-cell clones ex vivo, in peripheral blood and at tumor sites, in two long-term melanoma survivors. MAGE-A10-specific CD8⁺ T-cell clones with high avidity to antigenic peptide and tumor lytic capabilities persisted in peripheral blood over more than 10 years, with quantitative variations correlating with the clinical course. These clones were also found in emerging metastases, and, in one patient, circulating clonal T cells displayed a fully differentiated effector phenotype at the time of relapse. Longevity, tumor homing, differentiation phenotype, and quantitative adaptation to the disease phases suggest the contribution of the tracked tumor-reactive clones in the tumor control of these long-term metastatic survivor patients. Focusing research on patients with favorable outcomes may help to identify parameters that are crucial for an efficient antitumor response and to optimize cancer immunotherapy.