Cowpea Mosaic Virus Promotes Anti-Tumor Activity and Immune Memory in a Mouse Ovarian Tumor Model
Cowpea Mosaic Virus Promotes Anti-Tumor Activity and Immune Memory in a Mouse Ovarian Tumor Model
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DOI：
10.1002/adtp.201900003
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发表时间：
2019-05-01
影响因子：
4.6
通讯作者：
Steinmetz, Nicole F.
中科院分区：
文献类型：
--
作者：
Wang, Chao;Fiering, Steven N.;Steinmetz, Nicole F.
豇豆花叶病毒（CPMV）是一种有前途的平台纳米技术，可用作癌症治疗。为了更详细地理解CPMV的治疗潜力，使用同基因免疫活性鼠原位卵巢癌模型（ID 8-Defb 29/Vegf-A）研究其抗肿瘤机制。原位CPMV治疗促进肿瘤消退并预防肿瘤复发。虽然CPMV不直接杀死肿瘤细胞，但它促进肿瘤内细胞因子应答，诱导预先存在的骨髓细胞打破免疫耐受并启动抗肿瘤应答。观察到白细胞介素-6和干扰素-γ的上调以及IL-10和转化生长因子β的下调，与肿瘤相关巨噬细胞和嗜中性粒细胞活化和复极化为抗肿瘤表型相关。此外，原位施用CPMV将树突状细胞和自然杀伤细胞募集到肿瘤部位，并诱导CD 11b（-）髓样细胞上共刺激分子的表达。通过将免疫抑制性骨髓细胞转化为有效的抗原呈递细胞，原位CPMV治疗显著改善效应和记忆CD 4（+）和CD 8（+）T细胞应答，并促进全身肿瘤特异性细胞毒性CD 8（+）T细胞活性。CPMV原位免疫治疗通过协调涉及中性粒细胞、巨噬细胞和T细胞的先天性和适应性免疫应答，在侵袭性卵巢肿瘤模型中诱导显著的肿瘤控制。
Cowpea mosaic virus (CPMV) is a promising platform nanotechnology with applications as a cancer therapeutic. To understand the therapeutic potential of CPMV in more detail, its antitumor mechanisms are investigated using a syngeneic immunocompetent murine orthotopic ovarian cancer model (ID8-Defb29/Vegf-A). CPMV treatment in situ promotes tumor regression and prevents tumor recurrence. Although CPMV does not kill tumor cells directly, it promotes an intra-tumoral cytokine response which induces pre-existing myeloid cells to break immunotolerance and initiate antitumor responses. The upregulation of interleukin-6 and interferon-gamma as well as the downregulation of IL-10 and transforming growth factor beta are observed, associated with activation and repolarization of tumor-associated macrophages and neutrophils to an anti-tumor phenotype. Furthermore, the in situ administration of CPMV recruits dendritic cells and natural killer cells to the tumor site, and induces the expression of costimulatory molecules on CD11b(-) myeloid cells. By converting immunosuppressive myeloid cells into potent antigen-presenting cells, in situ CPMV treatment significantly improves effector and memory CD4(+) and CD8(+) T cell responses and promoted systemic tumor-specific cytotoxic CD8(+) T cell activity. CPMV in situ immunotherapy induces significant tumor control in an aggressive ovarian tumor model by coordinating innate and adaptive immune responses involving neutrophils, macrophages, and T cells.