Generation of triacyl lipopeptide-modified glycoproteins by metabolic glycoengineering as the neoantigen to boost anti-tumor immune response.
Generation of triacyl lipopeptide-modified glycoproteins by metabolic glycoengineering as the neoantigen to boost anti-tumor immune response.
复制标题
通过代谢糖工程生成三酰脂肽修饰的糖蛋白作为新抗原来增强抗肿瘤免疫反应。
DOI：
10.7150/thno.60211
复制
发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Xiang R
中科院分区：
文献类型：
--
作者：
Zhao Y;Li S;Lv J;Liu Y;Chen Y;Liu Y;Chen X;Li J;Qin X;Wang X;Shi J;Shi Y;Xiang R
肿瘤特异性抗原（TSA）的缺乏和免疫耐受是肿瘤免疫治疗的两大障碍。目前的免疫检查点抑制剂（ICI）仅在有限的癌症患者亚群中显示出临床应答，这在一定程度上取决于可能产生新抗原的肿瘤细胞的突变负荷。在这里，我们的目的是产生新抗原MDP，以表现出更强的抗肿瘤功效。研究方法：在这项研究中，我们利用化学修饰的唾液酸前体四乙酰基-N-叠氮基乙酰基-甘露糖胺（AC 4 ManNAZ）来工程化肿瘤细胞膜上的糖蛋白，用于体内半抗原佐剂Pam 3CSK 4的共价连接，其最终产生新抗原，即，ManNAZ-DBCO-Pam 3CSK 4（MDP）对肿瘤细胞的作用。在乳腺癌和肺癌的同基因小鼠模型中证实了高标记效率、在肿瘤组织中相对特异性的生物分布和抗肿瘤功效。结果如下：MDP新抗原在荷瘤小鼠体内的产生显著地诱发体液和T细胞依赖的抗肿瘤免疫应答，导致对乳腺癌和肺癌同种异体移植物的生长的强烈抑制，并显著地延长荷瘤小鼠的存活。有趣的是，MDP新抗原能够显著增加癌细胞对ICI的敏感性，并极大地增强乳腺癌和肺癌的鼠模型中的抗肿瘤功效，其对单独使用抗PD 1抗体的免疫疗法显示无应答或低应答。结论：我们开发了一种简单的代谢糖工程方法，在肿瘤细胞上人工产生新抗原，以增强肿瘤细胞的免疫原性，这能够显著改善ICI的反应和临床结果。
The lack of tumor specific antigens (TSA) and the immune tolerance are two major obstacles for the immunotherapy of cancer. Current immune checkpoint inhibitors (ICIs) show clinical responses in only limited subsets of cancer patients, which, to some extent, depends on the mutation load of tumor cells that may generate neoantigens. Here, we aimed to generate a neoantigen MDP to exhibit stronger anti-tumor efficacy. Methods: In this study, we utilized chemically modified sialic acid precursor tetra acetyl-N-azidoacetyl-mannosamine (AC4ManNAZ) to engineer the glycoproteins on the membranes of tumor cells for the covalent ligation of hapten adjuvant Pam3CSK4 in vivo, which eventually generated a neoantigen, i.e., ManNAZ-DBCO-Pam3CSK4 (MDP), on tumor cells. The high labeling efficiency, relatively specific biodistribution in tumor tissues and the anti-tumor efficacy were confirmed in the syngeneic murine models of the breast cancer and the lung cancer. Results: The generation of MDP neoantigen in tumor-bearing mice significantly evoked both the humoral and the T-cell-dependent antitumor immune responses, resulting in a strong inhibition on the growth of the breast cancer and the lung cancer allografts and significantly prolonged survival of tumor-bearing mice. Interestingly, MDP neoantigen was able to dramatically increase the sensitivity of cancer cells to ICIs and greatly enhance the anti-tumor efficacy in the murine models of both breast cancer and the lung cancer, which showed no or low responses to the immunotherapy with anti-PD1 antibody alone. Conclusions: We developed a simple metabolic glycoengineering method to artificially generate neoantigens on tumor cells to enhance tumor cell immunogenicity, which is able to significantly improve the response and the clinical outcome of ICIs.