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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Front. Med.    2021, Vol. 15 Issue (2) : 170-177    https://doi.org/10.1007/s11684-020-0747-z
REVIEW
Immune response triggered by the ablation of hepatocellular carcinoma with nanosecond pulsed electric field
Jianpeng Liu, Xinhua Chen, Shusen Zheng()
Division of Hepatobiliary Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Key Laboratory of Organ Transplantation, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
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Abstract

Nanosecond pulsed electric field (nsPEF) is a novel, nonthermal, and minimally invasive modality that can ablate solid tumors by inducing apoptosis. Recent animal experiments show that nsPEF can induce the immunogenic cell death of hepatocellular carcinoma (HCC) and stimulate the host’s immune response to kill residual tumor cells and decrease distant metastatic tumors. nsPEF-induced immunity is of great clinical importance because the nonthermal ablation may enhance the immune memory, which can prevent HCC recurrence and metastasis. This review summarized the most advanced research on the effect of nsPEF. The possible mechanisms of how locoregional nsPEF ablation enhances the systemic anticancer immune responses were illustrated. nsPEF stimulates the host immune system to boost stimulation and prevail suppression. Also, nsPEF increases the dendritic cell loading and inhibits the regulatory responses, thereby improving immune stimulation and limiting immunosuppression in HCC-bearing hosts. Therefore, nsPEF has excellent potential for HCC treatment.
Keywords nanosecond pulsed electric fields (nsPEF)      hepatocellular carcinoma (HCC)      immune response      recurrence      metastasis     
Corresponding Author(s): Shusen Zheng   
Just Accepted Date: 16 October 2020   Online First Date: 12 November 2020    Issue Date: 23 April 2021
 Cite this article:   
Jianpeng Liu,Xinhua Chen,Shusen Zheng. Immune response triggered by the ablation of hepatocellular carcinoma with nanosecond pulsed electric field[J]. Front. Med., 2021, 15(2): 170-177.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0747-z
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I2/170
ResearchersYearnsPEF parametersExperimental animals and cell lineImmune response
Nuccitelli et al. [16]20122000 pulses each, 100 ns long, and 30 kV/cm at a rate of 5–7 pulsesC57/BL6-HGF/SF transgenic mice with melanomas induced by UV radiationElevated CD4+ T cells have been detected in tumor
Chen et al. [15]20141000 pulses each, 100 ns long, and 50 kV/cm with repetition rates of 1 HzOrthotopic HCC model established in rats using N1–S1 HCC cellsPresence of Granzyme-B expressing cells in the tumor
Chen et al. [14]2014300 pulses each, 100 ns long in 0.5 HzAnimal model of human subdermal xenograft HCCLM3 cells in BALB/c nude mouseMacrophage infiltration in tumor
Nuccitelli et al. [40]2015(1) 400 pulses each, 100 ns long, and 15 kV/cm in delivering 50 A
(2) 500 pulses each, 100 ns, and 50 kV/cm		(1) Orthotopic HCC model established in rats using McA-RH7777 cells
(2) C57BL/6 female mice and B6 albino female mice along with the isogenic MCA205 fibrosarcoma cell line		Triggered a CD8-dependant inhibition of secondary tumor growth
Skeate et al. [38]2018Each 100 ns long and 30 kV/cm at a rate of 3 pulsesHuman papillomavirus type 16 (HPV16)-transformed C3.43 mouse tumor cell modelInduced an antitumor response driven by CD8+ T cells
Guo et al. [18]2018300–1000 pulses each, 100 ns long, and 50 kV/cm with the frequency of 1–2 HzFemale Balb/c mice with 4T1 cell lineDestruction of suppressive tumor microenvironment (TME); activation of antigen-presenting cells and induction of a potent antitumor memory response
Lassiter et al. [39]20181000 pulses (1–3 pulses/s) each, 100 ns long, and 48–52 kV/cmOrthotopic HCC model established in rats using N1–S1 HCC cellsActivated innate and adaptive immune memory
Guo et al. [17]2018600–1200 pulses each, 200 ns long, and 30 kV/cm in 2 HzFemale C57BL/6 mice with Pan02 cellsThe number of immune cells in the TME was changed and multiple activation markers were upregulated
Tab.1  Significant findings from preclinical nsPEF studies
Fig.1  Possible mechanism of the nsPEF-induced immune response. Abbreviations: nsPEF, nanosecond pulsed electric field; TAA, tumor-associated antigens; DC, dendritic cells; Tc, effector toxic T cells; Tm, memory T cells; TME, tumor microenvironment; ICD, immunogenic cell death; ER, endoplasmic reticulum; ROS, reactive oxygen species; DAMPs, danger-associated molecular patterns; HMGB1, high mobility group box 1.
NsPEFRFACryoablationMWA
Fundamental principlesUtilizing nsPEF to stimulate cell membrane and subcellular structures to produce membrane perforationUtilizing high-frequency alternating current to generate high temperaturesUtilizing liquefied gases to induce the freezing–thawing cycle of targeted lesionsUtilizing electromagnetic waves to generate heat
Treatment temperatureNonthermal60–100 °C<−40 °C>100 °C
Mechanism of tumor cell injuryApoptosis and immunogenic cell deathCentral area necrosis, peripheral area necrosis, or apoptosisCentral area necrosis, peripheral area necrosis, or apoptosisMainly necrosis
Released signalsDAMPs: CRT, ATP secretion, and HMGB1Intracellular antigens and DAMPs such as HSPs and HMGB1Preserved intracellular organelles, antigens, and DAMPs such as DNA and HSPsDAMPs: HSPs
Immune response(1) The number of immune cells in the TME was changed, and multiple activation markers were upregulated
(2) Elevated CD4+ T and CD8+ T cells were detected, and a CD8+-dependent inhibition of secondary tumor growth was triggered
(3) Activation of antigen-presenting cells and induction of a potent antitumor memory response		(1) Levels of interleukin-1b (IL-1b), IL-6, IL-8, and TNF were increased
(2) The increasing levels of CD4+ and CD8+ T cells, and the decreasing levels of CD25+, FoxP3+, and regulatory T cells		(1) Activating the nuclear factor κ-light-chain-enhancer of activated B cells (NF-kb) pathway
(2) Stimulating T cells and promoting a systemic immune response
(3) Levels of serum IL-1, IL-6, NF-kb, and TNF-a were increased.		The increasing levels of IL-1 and IL-6
Tab.2  Comparison of the immune response induced by nsPEF and thermal ablation
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