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Epigenetic Mechanisms Dictating Eradication of Cancer by Natural Killer Cells.

ABSTRACT: Natural killer (NK) cells of the innate immune system are the first line of defense against infectious agents and cancer cells. However, only a few mechanisms that regulate eradication of tumors by NK cells have been identified. In this review, we present an account of epigenetic mechanisms that modulate the ability of NK cells to eradicate cancer cells. To date, several drugs that target epigenetic modifiers have shown clinical efficacy in cancer. Therefore, once a given epigenetic modifier is validated as a regulator of NK cell function, it can be targeted for NK cell-based cancer immunotherapies.

SUBMITTER: Bugide S

PROVIDER: S-EPMC6085095 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Epigenetic Mechanisms Dictating Eradication of Cancer by Natural Killer Cells.

Bugide Suresh S Janostiak Radoslav R Wajapeyee Narendra N

Trends in cancer 20180703 8

Natural killer (NK) cells of the innate immune system are the first line of defense against infectious agents and cancer cells. However, only a few mechanisms that regulate eradication of tumors by NK cells have been identified. In this review, we present an account of epigenetic mechanisms that modulate the ability of NK cells to eradicate cancer cells. To date, several drugs that target epigenetic modifiers have shown clinical efficacy in cancer. Therefore, once a given epigenetic modifier is ...[more]

PMID: 30064663

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Project description:Extracellular vesicles (EVs) are secreted membrane vesicles, which play complex physiological and pathological functions in intercellular communication. Recently, we isolated natural killer (NK) cell-derived EVs (NK-EVs) from ex vivo expansion of NK cell cultures. The isolated NK-EVs contained cytotoxic proteins and several activated caspases, and they induced apoptosis in target cells. In this report, the protein levels of cytotoxic proteins from NK-EV isolates were analysed by ELISA. The mean values of perforin (PFN, 550 ng/mL), granzyme A (GzmA, 185 ng/mL), granzyme B (GzmB, 23.4 ng/mL), granulysin (GNLY, 56 ng/mL), and FasL (2.5 ng/mL) were obtained from >60 isolations using dot plots. The correlation between cytotoxicity and cytotoxic protein levels was examined by linear regression. PFN, GzmA, GzmB, GNLY all had a positive, moderate correlation with cytotoxicity, suggesting that there is not a single cytotoxic protein dominantly involved in killing and that all of these proteins may contribute to cytotoxicity. To further explore the possible killing mechanisms, cells were treated with NK-EVs, proteins extracted and lysates assessed by Western blotting. The levels of Gzm A substrates, SET and HMG2, were diminished in targeted cells, indicating that GzmA may induce a caspase-independent death pathway. Also, cytochrome C was released from mitochondria, a central hallmark of caspase-dependent death pathways. In addition, several ER-associated proteins were altered, suggesting that NK-EVs may induce ER stress resulting in cell death. Our results indicate that multiple killing mechanisms are activated by NK-derived EVs, including caspase-independent and -dependent cell death pathways, which can mediate cytotoxicity against cancer cells. Abbreviations: NK: natural killer cells; aNK: activated NK cells; EV: extracellular vesicles; ER: endoplasmic reticulum; ALL: acute lymphoblastic leukaemia; FBS: foetal bovine serum. GzmA: granzyme A; GzmB: granzyme B; GNLY: granulysin; PFN: perforin.

Dataset Information

Epigenetic Mechanisms Dictating Eradication of Cancer by Natural Killer Cells.

Publications

Epigenetic Mechanisms Dictating Eradication of Cancer by Natural Killer Cells.

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