title: Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.
abstract: Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research and Multidisciplinary Oncology Center, University Hospital (Centre Hospitalier Universitaire Vaudois), Lausanne, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.forename: Pascal
authors.initials: P
authors.lastname: Batard
authors.forename: Verena
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: Gilles
authors.initials: G
authors.lastname: Bioley
authors.forename: Danielle
authors.initials: D
authors.lastname: Liénard
authors.forename: Ferdy
authors.initials: F
authors.lastname: Lejeune
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Norbert
authors.initials: N
authors.lastname: Meidenbauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Norbert
authors.initials: N
authors.lastname: Lubenow
authors.forename: Daniel
authors.initials: D
authors.lastname: Speiser
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Mikaël J
authors.initials: MJ
authors.lastname: Pittet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008207:Lymphatic Metastasis; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000556:secondary; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D015851:Interleukin-7; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell