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
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.
2000 pulses each, 100 ns long, and 30 kV/cm at a rate of 5–7 pulses
C57/BL6-HGF/SF transgenic mice with melanomas induced by UV radiation
Elevated CD4+ T cells have been detected in tumor
Chen et al. [15]
2014
1000 pulses each, 100 ns long, and 50 kV/cm with repetition rates of 1 Hz
Orthotopic HCC model established in rats using N1–S1 HCC cells
Presence of Granzyme-B expressing cells in the tumor
Chen et al. [14]
2014
300 pulses each, 100 ns long in 0.5 Hz
Animal model of human subdermal xenograft HCCLM3 cells in BALB/c nude mouse
Macrophage 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]
2018
Each 100 ns long and 30 kV/cm at a rate of 3 pulses
Human papillomavirus type 16 (HPV16)-transformed C3.43 mouse tumor cell model
Induced an antitumor response driven by CD8+ T cells
Guo et al. [18]
2018
300–1000 pulses each, 100 ns long, and 50 kV/cm with the frequency of 1–2 Hz
Female Balb/c mice with 4T1 cell line
Destruction of suppressive tumor microenvironment (TME); activation of antigen-presenting cells and induction of a potent antitumor memory response
Orthotopic HCC model established in rats using N1–S1 HCC cells
Activated innate and adaptive immune memory
Guo et al. [17]
2018
600–1200 pulses each, 200 ns long, and 30 kV/cm in 2 Hz
Female C57BL/6 mice with Pan02 cells
The number of immune cells in the TME was changed and multiple activation markers were upregulated
Tab.1
Fig.1
NsPEF
RFA
Cryoablation
MWA
Fundamental principles
Utilizing nsPEF to stimulate cell membrane and subcellular structures to produce membrane perforation
Utilizing high-frequency alternating current to generate high temperatures
Utilizing liquefied gases to induce the freezing–thawing cycle of targeted lesions
Utilizing electromagnetic waves to generate heat
Treatment temperature
Nonthermal
60–100 °C
<−40 °C
>100 °C
Mechanism of tumor cell injury
Apoptosis and immunogenic cell death
Central area necrosis, peripheral area necrosis, or apoptosis
Central area necrosis, peripheral area necrosis, or apoptosis
Mainly necrosis
Released signals
DAMPs: CRT, ATP secretion, and HMGB1
Intracellular antigens and DAMPs such as HSPs and HMGB1
Preserved intracellular organelles, antigens, and DAMPs such as DNA and HSPs
DAMPs: 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
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