Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion
Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion
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DOI：
10.1111/j.1349-7006.2010.01583.x
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发表时间：
2010-07-01
期刊：
影响因子：
5.7
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Akazawa, Takashi;Inoue, Norimitsu;Seya, Tsukasa
开发有效的免疫佐剂对肿瘤免疫治疗具有重要意义。牛分枝杆菌Calmette-Guerin细胞壁骨架（BCG-CWS）在肿瘤免疫治疗中的应用已经在各种临床应用中得到了检验。由于BCG-CWS是一种无法化学合成的大分子，因此开发一种替代的合成分子是必要的，以确保佐剂的持续供应。本研究基于巨噬细胞活化脂肽(MALP)-2的结构设计了一种新的佐剂，MALP -2是一种类似BCG-CWS的toll样受体(TLR)-2配体。巨噬细胞激活脂肽-2，[S-（2,3-双棕榈酰氧基丙基）Cys (P2C) - GNNDESNISFKEK]，最初在支原体中发现，是一种可以化学合成的脂肽。一个MALP-2肽被一个功能基序RGDS取代，形成一个名为P2C-RGDS的新分子。选择RGDS是因为其序列构成整合素结合基序，并且多种整合素在包括树突状细胞（dc）在内的免疫细胞中表达。因此，这个基序增加了配体的功能。在体外较短的孵育时间内，P2C-RGDS比MALP-2更有效地激活DCs和脾细胞，RGDS基序有助于它们的激活。此外，P2C-RGDS在诱导dc向引流淋巴结迁移和抑制肿瘤生长方面的活性高于MALP-2。这种设计和开发合成佐剂的过程被称为“佐剂工程”，对P2C-RGDS的评价和改进是未来开发更强的合成佐剂的第一步。（癌症科学2010）。
The development of effective immunoadjuvants for tumor immunotherapy is of fundamental importance. The use of Mycobacterium bovis bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) in tumor immunotherapy has been examined in various clinical applications. Because BCG-CWS is a macromolecule that cannot be chemically synthesized, the development of an alternative synthetic molecule is necessary to ensure a constant supply of adjuvant. In the present study, a new adjuvant was designed based on the structure of macrophage-activating lipopeptide (MALP)-2, which is a Toll-like receptor (TLR)-2 ligand similar to BCG-CWS. Macrophage-activating lipopeptide-2, [S-(2,3-bispalmitoyloxypropyl)Cys (P2C) - GNNDESNISFKEK], originally identified in a Mycoplasma species, is a lipopeptide that can be chemically synthesized. A MALP-2 peptide was substituted with a functional motif, RGDS, creating a novel molecule named P2C-RGDS. RGDS was selected because its sequence constitutes an integrin-binding motif and various integrins are expressed in immune cells including dendritic cells (DCs). Thus, this motif adds functionality to the ligand. P2C-RGDS activated DCs and splenocytes more efficiently than MALP-2 over short incubation times in vitro, and the RGDS motif contributed to their activation. Furthermore, P2C-RGDS showed higher activity than MALP-2 in inducing migration of DCs to draining lymph node, and in inhibiting tumor growth in vivo. This process of designing and developing synthetic adjuvants has been named "adjuvant engineering," and the evaluation and improvement of P2C-RGDS constitutes a first step in the development of stronger synthetic adjuvants in the future. (Cancer Sci 2010).