Abstract
Immunotherapy is an alternative for metastatic melanoma patients resistant to chemotherapy. Natural killer (NK) cells are powerful antileukemia effectors and their role in solid tumors is suspected. NK cell activation is regulated by a balance between activating receptors, which detect stress molecules on tumor cells, and HLA-I specific inhibitory receptors. Here, we studied the phenotype and function of NK cells in stage IV metastatic melanoma patients. Circulating NK cells from 35 healthy donors and 51 patients were studied: 24 patients before chemotherapy (prechemotherapy), 17 patients 1 month after 1 to 4 lines of chemotherapy (postchemotherapy), and 10 patients analyzed pre- and postchemotherapy. NK functionality was carried out toward 2 primary metastatic melanoma cell lines, analyzed for the expression of NK receptor ligands. NK cells from prechemotherapy patients exhibit an NKp46(dim)/NKG2A(dim) phenotype. In contrast, NK cells from postchemotherapy patients display high expression of NKp46 and NKG2A receptors. Purified NK cells from patients are efficiently activated in response to melanoma cells. Melanoma cells express different level of NKG2D ligands and HLA-I molecules. In agreements with their phenotype, NK cells from pre- and postchemotherapy patients present distinct functional status toward these primary melanoma cells. A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells. These results provide new arguments and clues to design NK cell-based immunotherapeutic strategies for melanoma patients.
Highlights
Melanomas are highly metastatic tumors for which the treatment is still unsatisfactory
Purified Natural killer (NK) cells from patients are efficiently activated in response to melanoma cells
A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2–activated NK cells
Summary
Melanomas are highly metastatic tumors for which the treatment is still unsatisfactory. Besides antigen-specific T cells, natural killer (NK) cells are potent cytolytic effectors that play a role in the innate and adaptive antitumor immune responses. As they can be efficiently expanded in vitro, NK cells can be used in autologous and allogeneic settings and constitute interesting reagents for adoptive cellular therapy. First identified as a distinct subpopulation of lymphocytes endowed with the capacity to kill tumor cells without prior sensitization, NK cells are considered as highly sophisticated detectives of harmful changes in cellular self- and pivotal catalyzers of adaptive T-cell responses. NK cells are considered as the major source of IFN-g in vivo and NK-derived IFN-g is crucial in priming T helper 1 responses [6, 7]
Published Version
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