Blocking exposed PD-L1 elicited by nanosecond pulsed electric field reverses dysfunction of CD8+ T cells in liver cancer

Qian, Junjie; Chen, Tianchi; Wu, Qinchuan; Zhou, Lin; Zhou, Wuhua; Wu, Liming; Wang, Shuai; Lu, Jiahua; Wang, Qianqian; Li, Dazhi; Xie, Haiyang; Su, Rong; Guo, Danjing; Liu, Zhen; He, Na; Yin, Shengyong; Zheng, Shusen

doi:10.1016/j.canlet.2020.09.015

Cited by 15 publications

(13 citation statements)

References 50 publications

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“…Preclinical studies have shown that nsPEF could activate antitumor immunity [6,7,11], which corroborated with the findings in this study, However, the underlying mechanism remains to be elucidated. We started from examining the metabolomic and proteomic profiles of sera from patients that did not experience any tumor relapse up to 8 months after nsPEF.…”

Section: Safety and Efficacy Of Nspef Ablationsupporting

confidence: 91%

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2⁺ mononuclear phagocyte differentiation in liver cancer

et al. 2023

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Preclinical studies have proven that nanosecond pulsed electric field (nsPEF) ablation can be a safe and effective treatment for humans with unresectable liver cancer that are ineligible for thermal ablation. The concomitant activation of antitumor immunity by nsPEF can also potentially prevent tumor recurrence. However, whether nsPEF exhibits similar efficacy in a clinical setting remains to be investigated. A prospective clinical trial (http://clinicaltrials.gov identifier: NCT04039747) was conducted to evaluate the safety and efficacy of ultrasound (US)‐guided nsPEF ablation in 15 patients with unresectable liver cancer that were ineligible for thermal ablation. We found that nsPEF ablation was safe and produced a 12‐month recurrence‐free survival (RFS) and local RFS of 60% (9/15) and 86.7% (13/15), respectively, in the enrolled patients. Integrative proteomic and metabolomic analysis showed that sphingolipid metabolism was the most significantly enriched pathway in patient sera after nsPEF without recurrence within 8 months. A similar upregulation of sphingolipid metabolism was observed in the intratumoral mononuclear phagocytes (MNPs), rather than other immune and nonimmune cells, of an nsPEF‐treated mouse model. We then demonstrated that lymphocyte antigen 6 complex, locus C2‐positive (Ly6c2+) monocytes first differentiated into Ly6c2+ monocyte‐derived macrophages with an increase in sphingolipid metabolic activity, and subsequently into Ly6c2+ dendritic cells (DCs). Ly6c2+ DCs communicated with CD8+ T cells and increased the proportions of IFN‐γ+ CD8+ memory T cells after nsPEF, and this finding was subsequently confirmed by depletion of liver Ly6c2+ MNPs. In conclusion, nsPEF was a safe and effective treatment for liver cancer. The alteration of sphingolipid metabolism induced by nsPEF was associated with the differentiation of Ly6c2+ MNPs, and subsequently induced the formation of memory CD8+ T cells with potent antitumor effect.

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Section: Safety and Efficacy Of Nspef Ablationsupporting

confidence: 91%

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2⁺ mononuclear phagocyte differentiation in liver cancer

et al. 2023

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“…[12][13][14] For example, a study by Qian et al revealed that nPEF treatment upregulated the inhibitory ligand PDL1 in liver cancer cells, thereby impairing the function of CD8 + tumorinfiltrating lymphocytes (TILs) cells. [15] Consistent with this, our experimental results also confirmed elevated expression of PDL1 in tumor tissues following treatment with high-voltage pulsed electric field (Figure S1, Supporting Information). Hence, the synergistic combination of pulsed electric field (PEF) with immune checkpoint inhibitors targeting the PD1/PDL1 inhibitory pathway holds immense potential to significantly enhance the efficacy of antitumor immune responses, and this avenue is actively explored in current studies and ongoing clinical trials.…”

Section: Introductionsupporting

confidence: 88%

Optimal Irreversible Electroporation Combined with Nano‐Enabled Immunomodulatory to Boost Systemic Antitumor Immunity

Peng,

Cao,

Zhang

et al. 2023

Adv Healthcare Materials

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In this work, we proposed nµPEF, a novel pulse configuration combining nanosecond and microsecond pulses (nµPEF), to enhance tumor ablation in irreversible electroporation (IRE) for oncological therapy. nµPEF demonstrated improved efficacy in inducing immunogenic cell death, positioning it as a potential candidate for next‐generation ablative therapy. However, the immune response elicited by nµPEF alone was insufficient to effectively suppress distant tumors. To address this limitation, we developed PPR@CM‐PD1, a genetically engineered nanovesicle. PPR@CM‐PD1 employed a polyethylene glycol‐polylactic acid‐glycolic acid (PEG‐PLGA) nanoparticle encapsulating the immune adjuvant imiquimod and coated with a genetically engineered cell membrane expressing programmed cell death protein 1 (PD1). This design allowed PPR@CM‐PD1 to target both the innate immune system through toll‐like receptor 7 (TLR7) agonism and the adaptive immune system through programmed cell death protein 1/programmed cell death‐ligand 1 (PD1/PDL1) checkpoint blockade. In turn, nµPEF facilitated intratumoral infiltration of PPR@CM‐PD1 by modulating the tumor stroma. The combination of nµPEF and PPR@CM‐PD1 generated a potent and systemic antitumor immune response, resulting in remarkable suppression of both nµPEF‐treated and untreated distant tumors (abscopal effects). This interdisciplinary approach presents a promising perspective for oncotherapy and holds great potential for future clinical applications.

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“…More recently, combining nsPEFs with other treatments has also attracted interest. For example, drugs such as doxorubicin [ 29 ], paclitaxel [ 30 ], everolimus [ 31 ], and PD-L1 blockers [ 32 ] are combined with nsPEFs, and even infrared radiation is combined with nsPEFs.…”

Section: Discussionmentioning

confidence: 99%

Effects of Nanosecond Pulsed Electric Fields in Cell Vitality, Apoptosis, and Proliferation of TPC-1 Cells

Liu

Zou

Sun

et al. 2021

Analytical Cellular Pathology

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Objective. To evaluate the effects of nanosecond pulsed electric fields (nsPEFs) with different pulse durations in cell vitality, apoptosis, and proliferation of TPC-1 cells, optimize pulse parameters and expand the application range of nsPEFs. Methods. The pulse duration of 0, 300 ns, 500 ns, and 900 ns is generated with nsPEF generator. CCK-8 was used to investigate the effect of nsPEFs on the viability of TPC-1 cells. Flow cytometry was used to evaluate the apoptosis of TPC-1 after pulse treatment. The effect of nsPEFs on the proliferation ability of TPC-1 cells was detected by 5-ethy-nyl-2 ′ -deoxyuridine. The morphological changes of TPC-1 cells after pulse treatment were observed by transmission electron microscopy. Results. NsPEFs with 900 ns pulse duration can significantly affect the viability of TPC-1 cells and inhibit the proliferation ability of TPC-1 cells. In addition, nsPEFs can also induce apoptosis of TPC-1 cells. Conclusion. NsPEFs with longer pulse duration can significantly affect the biological behavior of TPC-1 cells, such as cell viability and proliferation ability, and can also induce cell apoptosis, thereby inhibiting cell growth.

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Blocking exposed PD-L1 elicited by nanosecond pulsed electric field reverses dysfunction of CD8+ T cells in liver cancer

Cited by 15 publications

References 50 publications

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2⁺ mononuclear phagocyte differentiation in liver cancer

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2⁺ mononuclear phagocyte differentiation in liver cancer

Optimal Irreversible Electroporation Combined with Nano‐Enabled Immunomodulatory to Boost Systemic Antitumor Immunity

Effects of Nanosecond Pulsed Electric Fields in Cell Vitality, Apoptosis, and Proliferation of TPC-1 Cells

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Blocking exposed PD-L1 elicited by nanosecond pulsed electric field reverses dysfunction of CD8+ T cells in liver cancer

Cited by 15 publications

References 50 publications

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2+ mononuclear phagocyte differentiation in liver cancer

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2+ mononuclear phagocyte differentiation in liver cancer

Optimal Irreversible Electroporation Combined with Nano‐Enabled Immunomodulatory to Boost Systemic Antitumor Immunity

Effects of Nanosecond Pulsed Electric Fields in Cell Vitality, Apoptosis, and Proliferation of TPC-1 Cells

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Product

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Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2⁺ mononuclear phagocyte differentiation in liver cancer

Nanosecond pulsed electric field ablation‐induced modulation of sphingolipid metabolism is associated with Ly6c2⁺ mononuclear phagocyte differentiation in liver cancer