Immunotherapy combining tumor and endothelium cell lysis with immune enforcement by recombinant MIP-3α Newcastle disease virus in a vessel-targeting liposome enhances antitumor immunity.
Immunotherapy combining tumor and endothelium cell lysis with immune enforcement by recombinant MIP-3α Newcastle disease virus in a vessel-targeting liposome enhances antitumor immunity.
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免疫疗法结合肿瘤和内皮细胞裂解与重组 MIP-3α 新城疫病毒在血管靶向脂质体中的免疫增强增强抗肿瘤免疫力
DOI：
10.1136/jitc-2021-003950
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Tan GH
中科院分区：
文献类型：
--
作者：
Wang JY;Chen H;Dai SZ;Huang FY;Lin YY;Wang CC;Li L;Zheng WP;Tan GH
几种溶瘤免疫治疗药物已被批准用于临床，但单一疗法对大多数溶瘤药物来说是适度的。通过重组和纳米技术将多种治疗策略相结合，以设计多功能溶瘤病毒进行溶瘤免疫治疗，是一种很有前途的策略。构建了表达树突状细胞趋化因子MIP-3α(α-LP)的重组新城疫病毒(NDV)内皮靶向IRGD型脂质体和3种对照脂质体。免疫印迹法或酶联免疫吸附试验检测MIP3α、HMGB1、Ig G、ATP值。Transwell小室检测DC的趋化活性。用流式细胞仪分析免疫细胞表型。用B16和4T1荷瘤小鼠观察其抗肿瘤作用。免疫荧光和免疫组织化学方法观察脂质体的定位、分子表达和血管生成情况。利用肿瘤体积、肿瘤血管生成、肿瘤浸润性淋巴细胞等指标计算协同指数。与新城疫病毒脂蛋白相比，新城疫病毒α-LP和新城疫病毒α-LP对B16、4T1肿瘤细胞和人脐静脉内皮细胞均有较强的病毒复制和细胞裂解作用，其中以iNDV3α-LP作用最强。经iNDV3α-LP处理的B16和4T1细胞产生了更多的损伤相关分子模式分子，包括分泌的HMGB1、三磷酸腺苷和钙网蛋白。此外，iNDV3α-LP可与表达αvβ3的4T1细胞、人脐静脉内皮细胞和肿瘤新生血管特异性结合。INDV3α-LP治疗的B16和4T1荷瘤小鼠的肿瘤生长受到显著抑制，存活时间更长。一项机制研究表明，iNDV3α-LP治疗启动了最强的肿瘤特异性细胞和体液免疫反应。此外，iNDV3α-LP治疗可显著抑制B16和4T1荷瘤小鼠的肿瘤血管生成，逆转肿瘤免疫抑制微环境。在本研究中，iNDV3α-LP具有肿瘤和血管溶解、α免疫治疗、与表达αvβ3的肿瘤及其新生血管结合等功能。INDV3α-LP治疗可明显抑制肿瘤血管生成，逆转肿瘤免疫抑制微环境。这些发现为进一步的临床研究肿瘤溶解免疫治疗的联合策略提供了强有力的理论基础，例如本研究中的iNDV3α-LP制剂。
Several agents for oncolytic immunotherapy have been approved for clinical use, but monotherapy is modest for most oncolytic agents. The combination of several therapeutic strategies through recombinant and nanotechnology to engineer multifunctional oncolytic viruses for oncolytic immunotherapy is a promising strategy. An endothelium-targeting iRGD-liposome encapsulating a recombinant Newcastle disease virus (NDV), which expresses the dendritic cell (DC) chemokine MIP-3α (iNDV3α-LP), and three control liposomes were constructed. MIP-3α, HMGB1, IgG, and ATP were detected by western blotting or ELISA. The chemotaxis of DCs was examined by Transwell chambers. The phenotypes of the immune cells were analyzed by flow cytometry. The antitumor efficiency was investigated in B16 and 4T1 tumor-bearing mice. Immunofluorescence and immunohistochemistry were used to observe the localization of liposomes, molecular expression and angiogenesis. Synergistic index was calculated using the data of tumor volume, tumor angiogenesis and tumor-infiltrating lymphocytes. Compared with NDV-LP, treatment with iNDV3α-LP and NDV3α-LP induced stronger virus replication and cell lysis in B16 and 4T1 tumor cells and human umbilical vein endothelial cells (HUVECs) with the best response observed following iNDV3α-LP treatment. B16 and 4T1 cells treated with iNDV3α-LP produced more damage-associated molecular pattern molecules, including secreted HMGB1, ATP, and calreticulin. Moreover, iNDV3α-LP specifically bound to αvβ3-expressing 4T1 cells and HUVECs and to tumor neovasculature. Tumor growth was significantly suppressed, and survival was longer in iNDV3α-LP-treated B16-bearing and 4T1-bearing mice. A mechanism study showed that iNDV3α-LP treatment initiated the strongest tumor-specific cellular and humoral immune response. Moreover, iNDV3α-LP treatment could significantly suppress tumor angiogenesis and reverse the tumor immune suppressive microenvironment in both B16-bearing and 4T1-bearing mice. In this study, iNDV3α-LP had several functions, such as tumor and vessel lysis, MIP-3α immunotherapy, and binding to αvβ3-expressing tumor and its neovasculature. iNDV3α-LP treatment significantly suppressed tumor angiogenesis and reversed the tumor immunosuppressive microenvironment. These findings offer a strong rationale for further clinical investigation into a combination strategy for oncolytic immunotherapy, such as the formulation iNDV3α-LP in this study.
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影响因子：
5.7
作者：
Lo JH;Hao L;Muzumdar MD;Raghavan S;Kwon EJ;Pulver EM;Hsu F;Aguirre AJ;Wolpin BM;Fuchs CS;Hahn WC;Jacks T;Bhatia SN
通讯作者：
Bhatia SN
影响因子：
5.8
作者：
Hamid, Omid;Ismail, Rubina;Puzanov, Igor
通讯作者：
Puzanov, Igor
影响因子：
10.1
作者：
Chiocca EA;Rabkin SD
通讯作者：
Rabkin SD
影响因子：
4.3
作者：
Cassidy, Tyler;Craig, Morgan
通讯作者：
Craig, Morgan
影响因子：
5.2
作者：
Ehrlich M;Bacharach E
通讯作者：
Bacharach E