Dataset Information

Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma.

ABSTRACT: An understanding of interactions within the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL) has helped pave the way to novel immunotherapies that have enabled dormant and tumor-tolerant immune cells to be reactivated. The immunosuppressive nature of the TME in cHL specifically inhibits the proliferation and activity of natural killer (NK) cells, which contributes to tumor immune-escape mechanisms. This deficiency of NK cells begins at the tumor site and progresses systemically in patients with advanced disease or adverse prognostic factors. Several facets of cHL account for this effect on NK cells. Locally, malignant Reed-Sternberg cells and cells from the TME express ligands for inhibitory receptors on NK cells, including HLA-E, HLA-G, and programmed death-ligand 1. The secretion of chemokines and cytokines, including soluble IL-2 receptor (sCD25), Transforming Growth Factor-?, IL-10, CXCL9, and CXCL10, mediates the systemic immunosuppression. This review also discusses the potential reversibility of quantitative and functional NK cell deficiencies in cHL that are likely to lead to novel treatments.

SUBMITTER: Chiu J

PROVIDER: S-EPMC5817071 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma.

Chiu Jodi J Ernst Daniel M DM Keating Armand A

Frontiers in immunology 20180214

An understanding of interactions within the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL) has helped pave the way to novel immunotherapies that have enabled dormant and tumor-tolerant immune cells to be reactivated. The immunosuppressive nature of the TME in cHL specifically inhibits the proliferation and activity of natural killer (NK) cells, which contributes to tumor immune-escape mechanisms. This deficiency of NK cells begins at the tumor site and progresses systemically in ...[more]

PMID: 29491867

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Project description:Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes that recognize and kill cancer cells. The susceptibility of target cancer cells to NK cell-mediated cytotoxicity depends on the strength and balance of regulatory (activating/inhibitory) ligands expressed on target cell surface. We performed gene expression arrays to determine patterns of NK cell ligands associated with B-cell non-Hodgkin lymphoma (b-NHL). Microarray analyses revealed significant upregulation of a multitude of NK-activating and costimulatory ligands across varied b-NHL cell lines and primary lymphoma cells, including ULBP1, CD72, CD48, and SLAMF6. To correlate genetic signatures with functional anti-lymphoma activity, we developed a dynamic and quantitative cytotoxicity assay in an integrated microfluidic droplet generation and docking array. Individual NK cells and target lymphoma cells were co-encapsulated in picoliter-volume droplets to facilitate monitoring of transient cellular interactions and NK cell effector outcomes at single-cell level. We identified significant variability in NK-lymphoma cell contact duration, frequency, and subsequent cytolysis. Death of lymphoma cells undergoing single contact with NK cells occurred faster than cells that made multiple short contacts. NK cells also killed target cells in droplets via contact-independent mechanisms that partially relied on calcium-dependent processes and perforin secretion, but not on cytokines (interferon-? or tumor necrosis factor-?). We extended this technique to characterize functional heterogeneity in cytolysis of primary cells from b-NHL patients. Tumor cells from two diffuse large B-cell lymphoma patients showed similar contact durations with NK cells; primary Burkitt lymphoma cells made longer contacts and were lysed at later times. We also tested the cytotoxic efficacy of NK-92, a continuously growing NK cell line being investigated as an antitumor therapy, using our droplet-based bioassay. NK-92 cells were found to be more efficient in killing b-NHL cells compared with primary NK cells, requiring shorter contacts for faster killing activity. Taken together, our combined genetic and microfluidic analysis demonstrate b-NHL cell sensitivity to NK cell-based cytotoxicity, which was associated with significant heterogeneity in the dynamic interaction at single-cell level.

Dataset Information

Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma.

Publications

Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma.

Similar Datasets

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