Irreversible electroporation induces CD8+ T cell immune response against post-ablation hepatocellular carcinoma growth

Dai, Zhengde; Wang, Zongren; Lei, Kai; Liao, Junbin; Peng, Zhenwei; Lin, Manxia; Liang, Ping; Yu, Jie; Peng, Sui; Chen, Shu‐Ling; Kuang, Ming

doi:10.1016/j.canlet.2021.01.001

Cited by 42 publications

(48 citation statements)

References 35 publications

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“…This specific hypothesis is not confirmed by literature, and there is still a window for any cells that survive partial ablation to proliferate and maintain the pro-tumor tumor microenvironment. However, this hypothesis is consistent with results following RFA, microwave ablation, and IRE, which can all reduce the presence of tumor supporting immune cells in the tumor microenvironment (7,122). This dynamic has also been seen in human patients.…”

Section: Decreases In Pro-tumor Immune Cellssupporting

confidence: 87%

Immunological Effects of Histotripsy for Cancer Therapy

et al. 2021

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Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.

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Section: Decreases In Pro-tumor Immune Cellssupporting

confidence: 87%

Immunological Effects of Histotripsy for Cancer Therapy

et al. 2021

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“…This process preserves adjacent structures by contributing to DC activation and maturation as well as immune cell infiltration. An increase in T-cell levels after IRE has been reported in several mouse models [114,115]. Recently, the combination of IRE and anti-PD1 treatment has been shown to promote selective tumor infiltration by CD8 + T cells, and to significantly suppress tumor growth and prolong survival of immunocompetent mice bearing pancreatic cancer and melanoma [116].…”

Section: Dcs and Irreversible Electroporationmentioning

confidence: 99%

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

Lucarini

Tempora

D’Amico

et al. 2021

Cancers

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Tumor-infiltrating CD8+ T cells have been shown to play a crucial role in controlling tumor progression. However, the recruitment and activation of these immune cells at the tumor site are strictly dependent on several factors, including the presence of dendritic cells (DCs), the main orchestrators of the antitumor immune responses. Among the various DC subsets, the role of cDC1s has been demonstrated in several preclinical experimental mouse models. In addition, the high density of tumor-infiltrating cDC1s has been associated with improved survival in many cancer patients. The ability of cDC1s to modulate antitumor activity depends on their interaction with other immune populations, such as NK cells. This evidence has led to the development of new strategies aimed at increasing the abundance and activity of cDC1s in tumors, thus providing attractive new avenues to enhance antitumor immunity for both established and novel anticancer immunotherapies. In this review, we provide an overview of the various subsets of DCs, focusing in particular on the role of cDC1s, their ability to interact with other intratumoral immune cells, and their prognostic significance on solid tumors. Finally, we outline key therapeutic strategies that promote the immunogenic functions of DCs in cancer immunotherapy.

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“…，而其它消融疗法如冷冻或热消融可导致蛋白变性，因此 IRE 消融后诱导形成的肿瘤抗原性较其它消融术后肿瘤抗原性更强，可诱导更强烈的免疫反应 [10][11] 。 Shao 等人 [11] 将 B16 黑色素瘤细胞经热 (50 [18][19][20] ；脾脏中 Treg 和 PD-1 + T 细胞减少，CD8 + IFN-γ + T 细胞比例增加 [18] ，外周血 CD8 + T 细胞比例均增多，而 Treg 比例明显下降 [19] 。Chen 等人 [21] 研究 [22] 。此外，IRE 消融诱导的免疫反应可抑制继发肿瘤的形成；研究人员使用 IRE-处理的 H22 细胞裂解物作为"疫苗"接种小鼠可预防小鼠肿瘤发生，而通过耗竭 IRE 治疗后 CD8 + T 细胞可诱导局部肿瘤再次生长和远处转移 [18] ，类似的研究也表明 nsPEF 消融肝癌可诱导 CD8 + T 细胞的产生，并且以 CD8 + 依赖性方式抑制继发性肿瘤生长 [22] 。Partridge 等人 [23]…”

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“…淋巴细胞的浸润。Guo 等人 [20] [24][25] ，诱导的巨噬细胞向 M1 型极化 [26] ，脾细胞中 CD8 + T 细胞和记忆 T 细胞比例显著增加 [25] 。此外，经 IRE 处理的肿瘤细胞上清液可抑制肿瘤的生长，且 IRE 诱导的免疫反应可抑制远隔部位肿瘤生长，表明 IRE 激活的系统性免疫应答具有全身性的抗肿瘤作用 [25] 。Narayanan 等人 [24] [24] ，提示检测方法对判断 IRE 介导的肿瘤免疫反应的特点有显著影响。两项临床研究发现 [27][28] IRE [18][19]29] 。(3)多项研究均在 IRE 与其它疗法联合治疗后对荷瘤机体的免疫细胞亚群进行了检测 [24,30] ，而其它疗法对机体免疫反应影 [31] 。IRE 消融局部肿瘤组织后濒死细胞的可释放大量的内源性危险信号分子，即损伤相关分子模式 (damage associated molecular patterns, DAMP)，驻留在肿瘤组织中的 DC 细胞可摄取这些抗原分子并迁移至引流淋巴结并重新激活肿瘤抗原特异性 T 细胞，影响免疫抑制性 T 细胞亚群的扩增，活化的肿瘤抗原特异性 T 细胞可能归巢到体内更远的部位消除转移灶，抑制肿瘤的进展 [32][33] 。大量研究表明，IRE 介导的细胞膜穿孔可增加 DAMP 的合成和分泌，如 ATP、HMGB1、钙网蛋白及 HSP70 等 [25-26, 30, 34] ，诱导肿瘤细胞的免疫原性细胞死亡，增强抗肿瘤免疫反应 [25] 。且 DAMP 的释放随着电场强度的增加而增加，其分泌水平与细胞死亡呈正相关 [34] 。He 等人 [26] [13,35] 。Zhao 等人 [30] [36][37] 。胸腺基质淋巴细胞生成素(TSLP)已被证实在多种肿瘤中可驱动免疫细胞向促癌免疫表型 Th2 型细胞极化 [38][39][40] ，Goswami 等人 [41] [42] ，对于肾癌的消融治疗是安全有效的，且具备对于小肾癌进行根治性治疗的潜力 [43] ；Distelmaier 等人 [44] 证实了 IRE 可用于邻近门静脉或肝静脉的肝脏肿瘤的消融治疗，不受热沉效应影响；Blazevski 等人 [45] 综述分析了 IRE 对 283 例前列腺癌患者的治疗效果，分析结果表明 91-100%的患者保留了控尿功能， 79-100%的男性保留了勃起功能，复发率为 0%-33%，提示 IRE 在有效清除肿瘤的同时还可保障患者的生活质量，是一种极具前景的前列腺癌的治疗方案。胰腺癌对免疫治疗不敏感与其高度免疫抑制的 TME 密切有关，Yang 等人 [46] 研究发现 [24,30] 。Neill 等人 [47] 研究发现 IRE 消融小鼠原位胰腺癌残存肿瘤细胞 PD-L1 的表达增加，并进一步采用 IRE 联合纳武单抗(FDA 批准的 PD-1 抑制剂临床用药)对 10 例 III 期不可手术切除的胰腺癌患者进行治疗，患者疾病进展的平均时间为 6.3 个月，中...…”

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