title: Phenotypic and functional characteristics of blood natural killer cells from melanoma patients at different clinical stages.
abstract: Melanomas are aggressive skin tumors characterized by high metastatic potential. Immunotherapy is a valuable alternative for metastatic melanoma patients resistant to chemotherapy. Natural Killer (NK) cells are efficient anti-tumor cytotoxic effectors. We previously showed that blood NK cells from stage IV metastatic melanoma patients display decreased NK receptors and that chemotherapy modifies the functional status of blood NK cells. To investigate the role of NK cells along melanoma progression, we have here studied NK cells from patients at different stages of the disease. First, we showed that ex vivo NK cells from certain stage III-IV patients displayed low degranulation potential. Using a dynamic label-free assay, we found that immunoselected IL-2 activated blood NK cells from patients efficiently lysed melanoma cells through NKp46 and NKG2D receptors, independently to the clinical stage. Moreover, the ex vivo phenotype of circulating NK cells from 33 patients (stage I to IV) was extensively analyzed. NK cells from patients displayed higher variability in the percentages of Natural Cytotoxicity Receptors (NCR) and Natural Killer Group 2D (NKG2D) receptor expression compared to donor NK cells. The main defect was the decreased expression of NCR1 (NKp46) by NK cells from metastatic patients. Interestingly, we found a positive correlation between the NK cell percentages of NKp46 and the duration of stage IV in melanoma patients. Finally, we showed that NK cells infiltrated primary melanomas and displayed a predominant peritumoral distribution. These results are new arguments for the development of NK-based therapies in melanoma patients.
authors.affiliation: Cochin Institute, Institut National de la Sante et de la Recherche Medicale (INSERM) U1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, University Paris Descartes, Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fregni
authors.forename: Meriem
authors.initials: M
authors.lastname: Messaoudene
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Fourmentraux-Neves
authors.forename: Sarra
authors.initials: S
authors.lastname: Mazouz-Dorval
authors.forename: Johan
authors.initials: J
authors.lastname: Chanal
authors.forename: Eve
authors.initials: E
authors.lastname: Maubec
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marinho
authors.forename: Isabelle
authors.initials: I
authors.lastname: Scheer-Senyarich
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cremer
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology / Q000378:metabolism; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: D007376:Interleukin-2; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1