Chimeric Trop2 Virus-like Particles: A Potential Immunotherapeutic Approach Against Pancreatic Cancer
Chimeric Trop2 Virus-like Particles: A Potential Immunotherapeutic Approach Against Pancreatic Cancer
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DOI：
10.1097/cji.0b013e318209ee72
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发表时间：
2011-04-01
影响因子：
3.9
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Cubas, Rafael;Zhang, Sheng;Yao, Qizhi
Trop 2是最近发现的在胰腺癌中过表达的细胞表面糖蛋白，其可潜在地用作免疫靶点。包膜病毒样颗粒（VLP）是高度免疫原性和多用途的免疫刺激剂，其可以被修饰以在其膜包膜上掺入外源蛋白以用作癌症疫苗。在这项研究中，我们研究了小鼠Trop 2（mTrop 2）VLP免疫在胰腺癌同基因小鼠模型中的作用。将掺入mTrop 2的VLP用于免疫C57 BL/6荷瘤小鼠。用mTrop 2 VLP免疫导致肿瘤生长显著减少，伴随着CD 4（+）和CD 8（+）T细胞以及自然杀伤和自然杀伤T细胞的广泛活化和肿瘤浸润。VLP免疫产生mTrop 2特异性细胞毒性T淋巴细胞和抗体，没有可测量的自身免疫诱导。重要的是，VLP免疫减少了肿瘤组织内的调节性T细胞和髓源性抑制细胞的数量，导致免疫抑制细胞因子如白细胞介素1 -0和转化生长因子-β的水平降低，同时促进未成熟巨噬细胞和树突状细胞的活化。此外，VLP免疫与吉西他滨治疗的组合显示出改善的效果，显著增加了荷瘤小鼠的存活。我们的研究结果表明，mTrop 2 VLP免疫可以激活广泛的抗肿瘤免疫应答，并影响肿瘤微环境中的关键参与者，克服限制癌症疫苗功效的主要障碍。这项研究提出了一种新的免疫治疗方法，可能用作胰腺癌患者联合治疗的替代治疗选择。
Trop2 is a recently discovered cell surface glycoprotein overexpressed in pancreatic cancer which could potentially be used as an immunotherapeutic target. Enveloped virus-like particles (VLPs) are highly immunogenic and versatile immune stimulatory agents which can be modified to incorporate exogenous proteins on their membrane envelope to use as cancer vaccines. In this study, we investigated the effects of murine Trop2 (mTrop2) VLP immunization in a pancreatic cancer syngeneic murine model. VLPs incorporating mTrop2 were used to immunize C57BL/6 tumor-bearing mice. Immunization with mTrop2 VLPs led to a significant reduction in tumor growth accompanied by a broad activation and tumor infiltration of CD4(+) and CD8(+) T cells as well as natural killer and natural killer T cells. VLP immunization generated mTrop2-specific cytotoxic T lymphocytes and antibodies with no measurable induction of autoimmunity. Importantly, VLP immunization decreased the population of regulatory T cells and myeloid-derived suppressor cells inside the tumor tissue resulting in decreased levels of immunosuppressive cytokines like interleukin1-0 and transforming growth factor-beta while promoting the activation of immature macrophages and dendritic cells. Furthermore, combination of VLP immunization with gemcitabine treatment showed an improved effect significantly increasing the survival of tumor bearing mice. Our results demonstrate that mTrop2 VLP immunization can activate broad antitumor immune responses and affect key players in the tumor microenvironment overcoming a major barrier, which has limited the efficacy of cancer vaccines. This study presents a novel immunotherapeutic approach which could potentially be used as an alternative treatment option in combination therapies to treat pancreatic cancer patients.