title: Circulating Tumor-reactive CD8(+) T cells in melanoma patients contain a CD45RA(+)CCR7(-) effector subset exerting ex vivo tumor-specific cytolytic activity.
abstract: To defend the host from malignancies, the immune system can spontaneously raise CD8(+) T-cell responses against tumor antigens. Investigating the 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-gamma 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.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital, 1005 Lausanne, Switzerland.
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
authors.forename: Carmen
authors.initials: C
authors.lastname: Scheibenbogen
authors.forename: Valerie
authors.initials: V
authors.lastname: Dutoit
authors.forename: Dirk
authors.initials: D
authors.lastname: Nagorsen
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Asemissen
authors.forename: Verena
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Danielle
authors.initials: D
authors.lastname: Liénard
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000097:blood / Q000276:immunology*; D014442:Monophenol Monooxygenase / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000097:blood / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: C515370:CCR7 protein, human; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D014442:Monophenol Monooxygenase; D017493:Leukocyte Common Antigens