Enhancing the Immunotherapeutic Effect by IP-001 and Irreversible Electroporation in Mouse Oligometastatic Models of Pancreatic Adenocarcinoma.

IF 3.4 2区 医学 Q2 ONCOLOGY
Annals of Surgical Oncology Pub Date : 2025-04-01 Epub Date: 2024-12-29 DOI:10.1245/s10434-024-16742-3
Yan Li, Samuel S K Lam, Yonglin Gao, Emily Shore, David W Anderson, Tomas Hode, Robert C Martin
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Abstract

Background: This study aimed to evaluate the immunotherapeutic effect of irreversible electroporation (IRE) and IP-001 in pancreatic adenocarcinoma with metastasis.

Methods: Orthotopic models of pancreatic adenocarcinoma with hepatic oligometastasis were established by implantation of tumor tissues (derived from Pan02 or KPC cells) size 2 mm3 into the pancreas and left liver lobe in C57BL/6J mice. One week after implantation, the tumor-burden mice were subjected to saline control, IRE, IP-001, and IRE+IP-001. For IRE therapy (1000 V, 0.1 ms, 10 pulses administered 10 times), the pancreas tumor was treated, whereas the oligometastasis was untreated as the IRE off-target tumor. Intratumoral administration of IP-001(0.4 ml/kg) was performed.

Results: In the KPC oligometastatic model, IRE+IP-001 therapy significantly suppressed the growth of oligometastatic tumor. Flow cytometry showed significantly increased tumor-infiltrating lymphocytes (TILs) (e.g., CD8+ cytotoxic T lymphocytes) and significantly increased monocytes/macrophages in the oligometastatic tumor tissues from IRE+IP-001 treatment compared with the sham control. Significantly decreased Treg cells and tumor-associated macrophages (TAMs) also were found in the oligometastatic tumor tissues from IRE+IP-001 treatment compared with the sham control. In the Pan02 oligometastatic model, both IRE+IP-001 therapy and IRE+anti-PD-L1 immunotherapy significantly suppressed the growth of oligometastatic tumor, which was associated with the increased CD8+ cytotoxic T lymphocytes. However, increased monocytes/macrophages were found in the mice that had IRE+IP-001 therapy, but not in the mice that had IRE+anti-PD-L1 immunotherapy.

Conclusion: The study provided compelling evidence for the efficacy of IRE&IP-001 therapy in suppressing pancreatic tumors, including off-target oligometastatic lesions. The observed off-target effect underscores the importance of systemic immune activation in achieving effective tumor control.

IP-001和不可逆电穿孔增强小鼠胰腺腺癌少转移模型的免疫治疗效果。
背景:本研究旨在评价不可逆电穿孔(IRE)和IP-001对转移性胰腺腺癌的免疫治疗效果。方法:在C57BL/6J小鼠胰腺和左肝叶分别植入2 mm3大小的肿瘤组织(来源于Pan02或KPC细胞),建立胰腺腺癌伴肝少转移原位模型。植入1周后,对肿瘤负荷小鼠进行生理盐水对照、IRE、IP-001和IRE+IP-001。对于IRE治疗(1000 V, 0.1 ms, 10次脉冲,给药10次),胰腺肿瘤被治疗,而少转移作为IRE脱靶肿瘤不治疗。瘤内给予IP-001(0.4 ml/kg)。结果:在KPC寡转移模型中,IRE+IP-001治疗可显著抑制寡转移瘤的生长。流式细胞术显示,与假对照组相比,IRE+IP-001治疗组低转移性肿瘤组织中肿瘤浸润淋巴细胞(TILs)(如CD8+细胞毒性T淋巴细胞)和单核/巨噬细胞显著增加。与假对照组相比,IRE+IP-001治疗的低转移性肿瘤组织中Treg细胞和肿瘤相关巨噬细胞(tam)也显著减少。在Pan02寡转移模型中,IRE+IP-001治疗和IRE+抗pd - l1免疫治疗均能显著抑制寡转移瘤的生长,这与CD8+细胞毒性T淋巴细胞的增加有关。然而,在接受IRE+IP-001治疗的小鼠中发现单核/巨噬细胞增加,而在接受IRE+抗pd - l1免疫治疗的小鼠中没有发现。结论:该研究为IRE&IP-001治疗胰腺肿瘤(包括脱靶少转移性病变)的抑制效果提供了令人信服的证据。观察到的脱靶效应强调了全身免疫激活在实现有效肿瘤控制中的重要性。
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来源期刊
CiteScore
5.90
自引率
10.80%
发文量
1698
审稿时长
2.8 months
期刊介绍: The Annals of Surgical Oncology is the official journal of The Society of Surgical Oncology and is published for the Society by Springer. The Annals publishes original and educational manuscripts about oncology for surgeons from all specialities in academic and community settings.
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