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Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells.

ABSTRACT: Natural killer (NK) cells have been shown to mediate important immunoregulatory "helper" functions in addition to their cytolytic activity. In particular, NK cells are capable of preventing maturation-related dendritic cell (DC) "exhaustion," inducing the development of "type-1 polarized" mature DCs (DC1) with an enhanced ability to produce interleukin (IL)-12p70, a factor essential for type-1 immunity and effective anticancer responses. Here we show that the NK cell-mediated type-1 polarization of DCs can be applied in the context of patients with advanced cancer to enhance the efficacy of DCs in inducing tumor-specific cytotoxic T lymphocytes. NK cells isolated from patients with late-stage (stage III and IV) melanoma responded with high interferon-? production and the induction of type-1-polarized DCs on exposure to defined combinations of stimulatory agents, including interferon-? and IL-18. The resulting DCs showed strongly-enhanced IL-12p70 production on subsequent T-cell interaction compared with immature DCs (average of 19-fold enhancement) and nonpolarized IL-1?/TNF-?/IL-6/PGE(2)-matured "standard" DCs (average of 215-fold enhancement). Additional inclusion of polyinosinic: polycytidylic acid during NK-DC cocultures optimized the expression of CD80, CD86, CD40, and HLA-DR on the resulting (NK)DC1, increased their CCR7-mediated migratory responsiveness to the lymph node-associated chemokine CCL21, and further enhanced their IL-12-producing capacity. When compared in vitro with immature DCs and nonpolarized standard DCs, (NK)DC1 were superior in inducing functional melanoma-specific cytotoxic T lymphocytes capable of recognizing multiple melanoma-associated antigens and killing melanoma cells. These results indicate that the helper function of NK cells can be used in clinical settings to improve the effectiveness of DC-based cancer vaccines.

SUBMITTER: Wong JL

PROVIDER: S-EPMC3057371 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells.

Wong Jeffrey L JL Mailliard Robbie B RB Moschos Stergios J SJ Edington Howard H Lotze Michael T MT Kirkwood John M JM Kalinski Pawel P

Journal of immunotherapy (Hagerstown, Md. : 1997) 20110401 3

Natural killer (NK) cells have been shown to mediate important immunoregulatory "helper" functions in addition to their cytolytic activity. In particular, NK cells are capable of preventing maturation-related dendritic cell (DC) "exhaustion," inducing the development of "type-1 polarized" mature DCs (DC1) with an enhanced ability to produce interleukin (IL)-12p70, a factor essential for type-1 immunity and effective anticancer responses. Here we show that the NK cell-mediated type-1 polarization ...[more]

PMID: 21389871

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Project description:BACKGROUND:Targeted therapies and immunotherapies are first-line treatments for patients with advanced melanoma. Serine-threonine protein kinase B-RAF (BRAF) and mitogen-activated protein kinase (MEK) inhibition leads to a 70% response rate in patients with advanced melanoma with a BRAFV600E /K mutation. However, acquired resistance occurs in the majority of patients, leading to relapse. Immunotherapies that activate immune cytotoxic effectors induce long-lasting responses in 30% of patients. In that context, combination of targeted therapies with immunotherapy (IT) is a promising approach. We considered boosting natural killer (NK) cell tumor immunosurveillance, as melanoma cells express stress-induced molecules and activate NK cell lysis. METHODS:Here we have generated vemurafenib (a BRAF inihibitor)-resistant (R) cells from BRAFV600E SK28 and M14-sensitive (S) melanoma cell lines and investigated how resistance interferes with immunogenicity to NK cells. We determined the levels of several soluble molecules including NK ligands in 61 melanoma patients at baseline and 6?months M post-treatment with targeted therapies or immunotherapies. RESULTS:Vemurafenib resistance involved activation of p-AKT in SK28R and of p-MEK/p-ERK in M14R cells and was accompanied by modulation of NK ligands. Compared with S cells, SK28R displayed an increased expression of natural killer group 2 D (NKG2D) receptor ligands (major histocompatibility complex class (MHC) I chain-related protein A (MICA) and UL16-binding protein 2 (ULBP2)) whereas M14R exhibited decreased ULBP2 . SK28R and M14R cells induced higher NK degranulation and interferon gamma secretion and were more efficiently lysed by donor and patient NK cells. SK28R showed increased tumor necrosis factor-related apoptosis-inducing ligand receptor II (TRAIL-RII) expression and TRAIL-induced apoptosis, and TRAIL-induced apoptosis of M14R was decreased. Combined BRAF/MEK inhibitors abrogated the growth of SK28S, M14S, and M14R cells, while growth of SK28R was maintained. BRAF/MEK inhibition attenuated NK activity but R cell lines activated polyfunctional NK cells and were lysed with high efficiency. We investigated the relationship of soluble NK ligands and response to treatment in a series of melanoma patients. Soluble NKG2D ligands known to regulate the receptor function have been associated to cancer progression. Serum analysis of patients treated with target therapies or IT indicates that soluble forms of NK ligands (MICA, B7H6, programmed cell death ligand 1, and carcinoembryonic antigen cell adhesion molecule 1) may correlate with clinical response. CONCLUSION:These results support strategies combining targeted therapies and NK-based immunotherapies.

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Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells.

Publications

Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells.

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