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Nanosecond-Pulsed DBD Plasma-Generated Reactive Oxygen Species Trigger Immunogenic Cell Death in A549 Lung Carcinoma Cells Through Intracellular Oxidative Stress

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Nanosecond-Pulsed DBD Plasma-Generated Reactive Oxygen Species Trigger Immunogenic Cell Death in A549 Lung Carcinoma Cells Through Intracellular Oxidative Stress International Journal of Molecular Sciences Article Nanosecond-Pulsed DBD Plasma-Generated Reactive Oxygen Species Trigger Immunogenic Cell Death in A549 Lung Carcinoma Cells through Intracellular Oxidative Stress Abraham Lin 1, Billy Truong 1, Sohil Patel 1, Nagendra Kaushik 2, Eun Ha Choi 2, Gregory Fridman 1, Alexander Fridman 1 and Vandana Miller 1,* 1 C. & J. Nyheim Plasma Institute, Drexel University, Philadelphia, PA 19104, USA; [email protected] (A.L.); [email protected] (B.T.); [email protected] (S.P.); [email protected] (G.F.); [email protected] (A.F.) 2 Plasma Bioscience Research Center, Kwangwoon University, Seoul 139791, Korea; [email protected] (N.K.); [email protected] (E.H.C.) * Correspondence: [email protected]; Tel.: +1-215-571-4074 Academic Editor: Hsueh-Wei Chang Received: 1 March 2017; Accepted: 28 April 2017; Published: 3 May 2017 Abstract: A novel application for non-thermal plasma is the induction of immunogenic cancer cell death for cancer immunotherapy. Cells undergoing immunogenic death emit danger signals which facilitate anti-tumor immune responses. Although pathways leading to immunogenic cell death are not fully understood; oxidative stress is considered to be part of the underlying mechanism. Here; we studied the interaction between dielectric barrier discharge plasma and cancer cells for oxidative stress-mediated immunogenic cell death. We assessed changes to the intracellular oxidative environment after plasma treatment and correlated it to emission of two danger signals: surface-exposed calreticulin and secreted adenosine triphosphate. Plasma-generated reactive oxygen and charged species were recognized as the major effectors of immunogenic cell death. Chemical attenuators of intracellular reactive oxygen species successfully abrogated oxidative stress following plasma treatment and modulated the emission of surface-exposed calreticulin. Secreted danger signals from cells undergoing immunogenic death enhanced the anti-tumor activity of macrophages. This study demonstrated that plasma triggers immunogenic cell death through oxidative stress pathways and highlights its potential development for cancer immunotherapy. Keywords: non-thermal plasma; cancer immunotherapy; immunogenic cell death; oxidative stress; calreticulin; adenosine triphosphate; plasma immunotherapy; nanosecond-pulsed dielectric barrier discharge 1. Introduction Methods to induce immunogenic cell death (ICD), where dying cells emit immuno-stimulatory signals, are being actively explored for cancer immunotherapy [1–5]. Cancerous cells undergoing ICD recruit and stimulate antigen presenting cells (APCs), key immune cells required for the initiation of an adaptive immune response [4–6]. This leads to the subsequent development and activation of tumor-specific effector T cells and memory T cells [7–9]. Thus, cancer is suppressed systemically and long-term protection against cancer recurrence is possible [8,9]. While mechanisms that promote ICD are under investigation, molecules characteristic of ICD known as damage-associated molecular patterns (DAMPs), have been identified [10,11]. These molecules are exposed on the cell surface or are secreted by cells undergoing autophagy, endoplasmic Int. J. Mol. Sci. 2017, 18, 966; doi:10.3390/ijms18050966 www.mdpi.com/journal/ijms Int.Int. J.J. Mol.Mol. Sci.Sci. 2017,, 18,, 966966 22 ofof 2424 reticulum (ER) stress, or oxidative stress from reactive oxygen species (ROS) [6,10–13]. DAMPs that reticulumare characteristically (ER) stress, or associated oxidative stresswith fromICD reactiveare: surface-exposed oxygen species calreticulin (ROS) [6,10 –(ecto-CRT),13]. DAMPs secreted that are characteristicallyadenosine triphosphate associated (ATP), with ICDreleased are: surface-exposedhigh mobility group calreticulin protein (ecto-CRT), B1 (HMGB1), secreted and adenosine surface- triphosphateexposed heat (ATP), shock released protein high90 (HSP90) mobility and group HSP70 protein [13–16]. B1 (HMGB1), Of these, andCRT surface-exposed and ATP are identified heat shock as proteinthe major 90 (HSP90)predictors and of HSP70 the [immuno-stimulatory13–16]. Of these, CRT capacity and ATP areof anti-cancer identified as therapeutics the major predictors [15–18]. ofRetrospective the immuno-stimulatory evaluation of capacityexperimental of anti-cancer and clinical therapeutics data has led [15 to– 18the]. identification Retrospective of evaluation several ICD of experimentalinducers, including and clinical some chemotherapeutics data has led to the identification(anthracyclines of and several oxaliplatin), ICD inducers, ionizing including radiation, some and chemotherapeuticsphotodynamic therapy (anthracyclines with hypericin and oxaliplatin),[1–3]. At the ionizing same time, radiation, new ICD and photodynamicinducers, such therapyas non- withthermal hypericin plasma, [1 are–3]. also At being the same investigated. time, new ICD inducers, such as non-thermal plasma, are also beingPlasma, investigated. known as the fourth state of matter, is an ionized gas composed of electrons, various ions,Plasma, electronically known excited as the fourthatoms stateand ofneutral matter, atoms is an and ionized molecules gas composed [19]. Two of electrons,major families various of ions,devices electronically for generating excited non-thermal atoms and neutralplasma atoms at at andmospheric molecules pressure [19]. Two for majorbiological families and of medical devices forapplications generating are non-thermal (Figure 1): plasma (1) plasma at atmospheric jets and pressure(2) direct for dielectric biological barrier and medical discharges applications (DBDs) are(employed (Figure1 in): (1)this plasma study) jets [20,21]. and (2)In directjets, most dielectric of the barrier plasma discharges is genera (DBDs)ted remotely, (employed and inplasma this study)products [20 are,21]. often In jets, delivered most of to the the plasma biological is generated target via remotely, a carrier andgas plasma[21]. Ionization products waves are often also deliveredproduce some to the plasma biological at targetthe treatment via a carrier surface gas [22] [21].. IonizationDBDs generate waves plasma also produce directly some at the plasma surface at thebeing treatment treated surface[20]. Due [22 ].to DBDs the electrode generate design, plasma directlyDBDs are at thetypically surface able being to treateda cover [ 20a ].much Due tolarger the electrodesurface area design, compared DBDs to are jets typically [23]. Furthermore, able to a cover the achemical much larger species surface deposited area compared on target surfaces, to jets [23 in]. Furthermore,particular, charged the chemical energetic species particles deposited and short-lived on target reactive surfaces, species, inparticular, are different charged between energetic the two particlessystems [20,21,24]. and short-lived reactive species, are different between the two systems [20,21,24]. FigureFigure 1.1. TwoTwo majormajor familiesfamilies ofof non-thermal,non-thermal, atmosphericatmospheric pressurepressure plasmaplasma devicesdevices forfor biomedicalbiomedical applicationsapplications areare jetsjets andand dielectricdielectric barrierbarrier dischargesdischarges (DBDs)(DBDs) ((AA)) JetsJets remotelyremotely generategenerate bulkbulk plasmaplasma andand plasmaplasma speciesspecies areare oftenoften transportedtransported toto thethe targettarget viavia aa carriercarrier gas;gas; ((BB)) DBDsDBDs plasmaplasma useuse thethe targettarget asas aa groundinggrounding electrodeelectrode toto generategenerate plasmaplasma directlydirectly ontoonto cells cells and and tissue. tissue. BesidesBesides thethe applied applied electric electric field field and plasmaand plasma temperature, temperature, a major determinanta major determinant of the composition of the ofcomposition plasma is theof plasma gas environment is the gas environment in which the in plasma whichis the generated plasma is [25 generated]. In the presence[25]. In the of presence oxygen, reactiveof oxygen, oxygen reactive species oxygen (ROS) species such (ROS) as atomic such oxygen as atomic (O), oxygen hydroxyl (O), radicals hydroxyl (•OH), radicals superoxide (•OH), superoxide− (O2•−), singlet1 oxygen (1O2), and hydrogen peroxide (H2O2) are produced [26–29]. When (O2• ), singlet oxygen ( O2), and hydrogen peroxide (H2O2) are produced [26–29]. When reactive nitrogenreactive nitrogen species (RNS)species are (RNS) desired are desired for wound for wound healing healing or other or specificother specific applications, applications, nitrogen nitrogen may bemay introduced be introduced into the into discharge the discharge environment environmen [30]. Majort [30]. measured Major measured species include species atomic include nitrogen atomic − (N),nitrogen peroxynitrite (N), peroxynitrite (ONOO− ),(ONOO and nitric), and oxide nitric (NO) oxide [31 (NO)]. Therefore, [31]. Theref it isore, plausible it is plausi to optimizeble to optimize plasma treatmentplasma treatment parameters parameters to produce to produce various chemicalvarious ch effectorsemical effectors for desired for biologicaldesired biological outcomes. outcomes. TheThe highlyhighly reactivereactive speciesspecies areare knownknown toto influenceinfluence biologicalbiological processesprocesses andand theirtheir rolerole inin cancercancer cellcell killingkilling hashas beenbeen extensivelyextensively researchedresearched [[32,33].32,33]. InIn fact,fact, chemotherapieschemotherapies andand radiationradiation therapytherapy oftenoften relyrely
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