title: Tissue homing and persistence of defined antigen-specific CD8+ tumor-reactive T-cell clones in long-term melanoma survivors.
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.
authors.affiliation: Laboratory of Tumor Immunology, Division of Oncology, Department of Internal Medicine, University Hospital, Geneva, Switzerland. frederique-anne.legal@hcuge.ch
authors.forename: Frédérique-Anne
authors.initials: FA
authors.lastname: Le Gal
authors.forename: Valérie M
authors.initials: VM
authors.lastname: Widmer
authors.forename: Valérie
authors.initials: V
authors.lastname: Dutoit
authors.forename: Verena
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: Jacques
authors.initials: J
authors.lastname: Schrenzel
authors.forename: Paul R
authors.initials: PR
authors.lastname: Walker
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Romero
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000276:immunology; D010641:Phenotype; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; C121012:MAGEA10 protein, human; D009363:Neoplasm Proteins