Surface-Presentation of CpG and Protein-Antigen on Pathogen-Like Polymer Particles Generate Strong Prophylactic and Therapeutic Antitumor Protection
Surface-Presentation of CpG and Protein-Antigen on Pathogen-Like Polymer Particles Generate Strong Prophylactic and Therapeutic Antitumor Protection
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DOI：
10.1021/acsbiomaterials.6b00384
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发表时间：
2017-02-01
影响因子：
5.8
通讯作者：
Roy, Krishnendu
中科院分区：
文献类型：
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作者：
Dawson, Eileen;Leleux, Jardin A.;Roy, Krishnendu
尽管做出了重大努力，但临床相关的预防性和治疗性癌症疫苗的开发已被证明具有挑战性。癌症相关抗原，通常是自身抗原，不能充分激活先天免疫细胞，强调需要适当的免疫刺激佐剂的共递送。最近的研究已经强调了对用于疫苗递送的基于生物材料的载体的需要，不仅将抗原和佐剂靶向抗原呈递细胞或产生“储库”样系统，而且避免当佐剂以其“裸”形式递送时发生的分子佐剂的急性全身毒性。本文介绍的工作重点是抗原和佐剂在病原体样颗粒（PLP）平台上的表面呈递，并了解当蛋白质抗原和佐剂（特别是TLR 9激动剂CpG）在同一颗粒（双负载）的表面上递送与在单独颗粒上共同递送时PLP诱导的抗肿瘤反应如何不同。表面呈递允许抗原和佐剂更容易接近细胞内靶（例如，至吞噬体隔室中的TLR 9），并且还允许受控的多价呈递。我们的研究结果表明，表面呈递，而不是可溶性分子，是更有效地激活树突状细胞（DC）和极化他们向产生更强的细胞毒性T细胞反应。单独和双负载颗粒之间的信号传导和DC极化是相似的，尽管在双负载PLPs中较高剂量的NF-κ B信号传导更强。在体内，双重负载的PLP在黑色素瘤的预防性肿瘤模型中比单独负载的PLP表现更好，并且与使用不完全弗洛伊德佐剂（IFA）的免疫相当。相比之下，两种基于PLP的递送方式在治疗性黑素瘤疫苗模型中表现相似，并且显著优于基于IFA的疫苗接种。这些结果表明，抗原和佐剂在聚合物颗粒上的表面呈递是有效的抗癌疫苗的一种有前途的方式。
Despite significant efforts, development of clinically relevant prophylactic and therapeutic cancer vaccines has proven challenging. Cancer-associated antigens, which are often self antigens, do not activate innate immune cells sufficiently, underscoring the need for codelivery of appropriate immune stimulatory adjuvants. Recent research has underscored the need for biomaterial-based carriers for vaccine delivery, not only to target antigens and adjuvants to antigen-presenting cells or to create "depot" like systems but also to avoid acute systemic toxicity of molecular adjuvants that occurs when adjuvants are delivered in their "naked" form. The work presented here focuses on surface presentation of both antigens and adjuvants on a pathogen-like particle (PLP) platform and understanding how PLP-induced antitumor responses differ when protein antigens and adjuvants, specifically the TLR9 agonist CpG, are delivered on the surface of the same particle (dual-loaded) versus being codelivered on separate particles. Surface-presentation allows easier access of antigens and adjuvants to intracellular targets (e.g., to TLR9 in the phagosomal compartments) and also allows controlled multivalent presentation. Our results show that, surface presentation, as opposed to soluble molecules, was more efficient in activating dendritic cells (DCs) and polarizing them toward generating a stronger cytotoxic T cell response. Signaling and DC polarization between separate and dual-loaded particles were similar, although NF-kappa B signaling at higher doses was stronger in dual-loaded PLPs. In vivo, dual loaded PLPs performed better than separately loaded PLPs in a prophylactic tumor model of melanoma and were comparable to immunization using incomplete Freud's adjuvant (IFA). In contrast both PLP-based delivery modalities performed similarly in a therapeutic melanoma-vaccine model and significantly outperformed IFA-based vaccination. These results indicate that surface-presentation of antigens and adjuvants on polymer-particles is a promising modality for efficient anticancer vaccines.