In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma.
In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma.
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DOI：
10.1021/acs.molpharmaceut.8b00316
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发表时间：
2018-09-04
影响因子：
4.9
通讯作者：
Steinmetz NF
中科院分区：
文献类型：
--
作者：
Murray AA;Wang C;Fiering S;Steinmetz NF
癌症免疫疗法已成为针对癌症的新型治疗方案。一个特别有趣的途径是原位疫苗接种的概念，其中将免疫刺激剂引入已识别的肿瘤中以克服局部免疫抑制，如果成功，则可以增强全身抗肿瘤免疫力。我们之前已经证明，豇豆花叶病毒（CPMV）的纳米颗粒在各种肿瘤小鼠模型中用作原位疫苗时，能够高效诱导持久的抗肿瘤免疫。在这里，我们询问烟草花叶病毒 (TMV) 的纳米颗粒是否也可以用作原位疫苗，如果可以，免疫激活的功效或机制是否会受到纳米颗粒尺寸（300 × 18 nm 天然 TMV 与 50 × 18 nm 短 TMV 纳米棒）、形状（纳米棒与球形 TMV，称为 SNP）或组装状态（组装 TMV 棒与游离外壳蛋白，CP）的影响。我们的研究表明，在对真皮黑色素瘤（使用 C57BL/6 小鼠的 B16F10）进行瘤内治疗后，CPMV（但 TMV 的效果较差）可引发有效的抗肿瘤免疫。 TMV 和 TMVshort 减缓了肿瘤生长并延长了生存时间，但与 CPMV 相比，其效力明显较低。 TMV、TMVshort 或 SNP 之间没有明显差异，表明长宽比不一定在植物病毒原位疫苗中发挥作用。游离的 CP 不会引起抗肿瘤反应或免疫刺激，这可能表明需要多价组装来触发先天免疫识别和激活。 CPMV 与 TMV 的功效差异可以用免疫激活的差异来解释：数据表明，CPMV 通过将单核细胞招募到肿瘤微环境 (TME) 中来刺激抗肿瘤反应，通过 IFN-γ 途径建立信号传导，这也导致肿瘤浸润的中性粒细胞 (TIN) 和自然杀伤 (NK) 细胞的招募。此外，先天免疫系统的启动也会通过 CD4+ 和 CD8+ T 细胞的招募和效应记忆细胞的建立来引发适应性反应。虽然 TMV 治疗也会导致先天免疫细胞和 T 细胞的募集（尽管程度较小），但在细胞/趋化因子分析方面注意到了关键差异，TMV 早期诱导了强效的免疫反应，其特征是强促炎细胞因子（主要是 IL-6）。总之，数据表明，一些植物病毒纳米技术平台比其他平台更适合用作原位疫苗；了解免疫激活的复杂差异和潜在机制可能为这些技术的临床开发奠定基础。
Cancer immunotherapy approaches have emerged as novel treatment regimens against cancer. A particularly interesting avenue is the concept of in situ vaccination, where immunostimulatory agents are introduced into an identified tumor to overcome local immunosuppression and, if successful, mount systemic antitumor immunity. We had previously shown that nanoparticles from cowpea mosaic virus (CPMV) are highly potent in inducing long-lasting antitumor immunity when used as an in situ vaccine in various tumor mouse models. Here we asked whether the nanoparticles from tobacco mosaic virus (TMV) could also be applied as an in situ vaccine and, if so, whether efficacy or mechanism of immune-activation would be affected by the nanoparticle size (300 × 18 nm native TMV vs 50 × 18 nm short TMV nanorods), shape (nanorods vs spherical TMV, termed SNP), or state of assembly (assembled TMV rod vs free coat protein, CP). Our studies indicate that CPMV, but less so TMV, elicits potent antitumor immunity after intratumoral treatment of dermal melanoma (B16F10 using C57BL/6 mice). TMV and TMVshort slowed tumor growth and increased survival time, however, at significantly lower potency compared to that of CPMV. There were no apparent differences between TMV, TMVshort, or the SNP indicating that the aspect ratio does not necessarily play a role in plant viral in situ vaccines. The free CPs did not elicit an antitumor response or immunostimulation, which may indicate that a multivalent assembly is required to trigger an innate immune recognition and activation. Differential potency of CPMV vs TMV can be explained with differences in immune-activation: data indicate that CPMV stimulates an antitumor response through recruitment of monocytes into the tumor microenvironment (TME), establishing signaling through the IFN-γ pathway, which also leads to recruitment of tumor-infiltrated neutrophils (TINs) and natural killer (NK) cells. Furthermore, the priming of the innate immune system also mounts an adaptive response with CD4+ and CD8+ T cell recruitment and establishment of effector memory cells. While the TMV treatment also lead to the recruitment of innate immune cells as well as T cells (although to a lesser degree), key differences were noted in cyto/chemokine profiling with TMV inducing a potent immune response early on characterized by strong pro-inflammatory cytokines, primarily IL-6. Together, data indicate that some plant viral nanotechnology platforms are more suitable for application as in situ vaccines than others; understanding the intricate differences and underlying mechanism of immune-activation may set the stage for clinical development of these technologies.
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影响因子：
8.8
作者：
Kratochvill F;Neale G;Haverkamp JM;Van de Velde LA;Smith AM;Kawauchi D;McEvoy J;Roussel MF;Dyer MA;Qualls JE;Murray PJ
通讯作者：
Murray PJ
影响因子：
16.6
作者：
Eber, Fabian J.;Eiben, Sabine;Wege, Christina
通讯作者：
Wege, Christina
影响因子：
3.7
作者：
FRAENKELCONRAT, H
通讯作者：
FRAENKELCONRAT, H
影响因子：
3.8
作者：
Atabekov, Joseph;Nikitin, Nikolai;Karpova, Olga
通讯作者：
Karpova, Olga
影响因子：
6.7
作者：
Eber, Fabian J.;Eiben, Sabine;Wege, Christina
通讯作者：
Wege, Christina