A Potent Cancer Vaccine Adjuvant System for Particleization of Short, Synthetic CD8(+) T Cell Epitopes.
A Potent Cancer Vaccine Adjuvant System for Particleization of Short, Synthetic CD8(+) T Cell Epitopes.
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DOI：
10.1021/acsnano.0c07680
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发表时间：
2021-03-23
期刊：
影响因子：
17.1
通讯作者：
Lovell, Jonathan F.
中科院分区：
文献类型：
--
作者：
He, Xuedan;Zhou, Shiqi;Huang, Wei-Chiao;Seffouh, Amal;Mabrouk, Moustafa T.;Morgan, M. Thomas;Ortega, Joaquin;Abrams, Scott, I;Lovell, Jonathan F.
短主要组织相容性复合体（MHC） I类（MHC-I）限制性肽含有诱导抗原（Ag）特异性CD8+细胞毒性T细胞反应的最低生化信息，但通常无效。为了解决这个问题，我们开发了一种钴卟啉（CoPoP）脂质体疫苗佐剂，它可以诱导传统的短合成MHC-I表位的快速颗粒化，从而在纳克剂量下产生强大的细胞免疫反应。与CoPoP（诱导多肽颗粒形成）一起，合成单磷酰脂质A （PHAD）和QS-21免疫刺激分子被纳入脂质体双分子层，形成“CPQ”佐剂体系。在小鼠中，用一种由糖蛋白70 （gp70）衍生的mhc - i限制性短肽与CPQ混合免疫，安全产生功能性ag特异性CD8+ T细胞，导致多种肿瘤细胞系的排斥反应，并具有持久的免疫力。当省略钴时，其他相同的肽和佐剂成分不会导致肽结合，也无法诱导免疫反应，这表明稳定颗粒形成的重要性。脂质体疫苗免疫耐受良好，可在治疗环境中控制局部和转移性疾病。机制研究表明，基于颗粒的肽更容易被抗原呈递细胞吸收，它们被推测在内体和吞噬体中释放，在MHC-I表面展示。基于该方法的效力，该平台被证明是一种包含100个肽的肽微文库的体内表位筛选工具。
Short major histocompatibility complex (MHC) class I (MHC-I)-restricted peptides contain the minimal biochemical information to induce antigen (Ag)-specific CD8+ cytotoxic T cell responses, but are generally ineffective in doing so. To address this, we developed a cobalt-porphyrin (CoPoP) liposome vaccine adjuvant that induces rapid particleization of conventional, short synthetic MHC-I epitopes, leading to strong cellular immune responses at nanogram dosing. Along with CoPoP (to induce particle formation of peptides), synthetic monophosphoryl lipid A (PHAD) and QS-21 immunostimulatory molecules were included in the liposome bilayer to generate the “CPQ” adjuvant system. In mice, immunization with a short MHC-I-restricted peptide, derived from glycoprotein 70 (gp70), admixed with CPQ safely generated functional, Ag-specific CD8+ T cells, resulting in the rejection of multiple tumor cell lines, with durable immunity. When cobalt was omitted, the otherwise identical peptide and adjuvant components did not result in peptide binding and were incapable of inducing immune responses, demonstrating the importance of stable particle formation. Immunization with the liposomal vaccine was well-tolerated and could control local and metastatic disease in a therapeutic setting. Mechanistic studies showed that particle-based peptides were better taken up by antigen-presenting cells, where they were putatively released within endosomes and phagosomes for display on MHC-I surfaces. Based on the potency of the approach, the platform was demonstrated as a tool for in vivo epitope screening of peptide micro-libraries comprising a hundred peptides.
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影响因子：
11.2
作者：
Kang TH;Mao CP;Lee SY;Chen A;Lee JH;Kim TW;Alvarez RD;Roden RB;Pardoll D;Hung CF;Wu TC
通讯作者：
Wu TC
影响因子：
38.3
作者：
Huang WC;Deng B;Lin C;Carter KA;Geng J;Razi A;He X;Chitgupi U;Federizon J;Sun B;Long CA;Ortega J;Dutta S;King CR;Miura K;Lee SM;Lovell JF
通讯作者：
Lovell JF
影响因子：
3.7
作者：
Heuts J;Varypataki EM;van der Maaden K;Romeijn S;Drijfhout JW;van Scheltinga AT;Ossendorp F;Jiskoot W
通讯作者：
Jiskoot W
影响因子：
9.2
作者：
Huang, Wei-Chiao;Deng, Bingbing;Lovell, Jonathan F.
通讯作者：
Lovell, Jonathan F.
影响因子：
4.4
作者：
Castle JC;Loewer M;Boegel S;de Graaf J;Bender C;Tadmor AD;Boisguerin V;Bukur T;Sorn P;Paret C;Diken M;Kreiter S;Türeci Ö;Sahin U
通讯作者：
Sahin U