Enhancement of tumor immunogenicity by the introduction of non- proteinogenic amino acid azetidine-2-carboxylic acid
Enhancement of tumor immunogenicity by the introduction of non- proteinogenic amino acid azetidine-2-carboxylic acid
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通过引入非蛋白氨基酸氮杂环丁烷-2-羧酸增强肿瘤免疫原性
DOI：
10.1080/2162402x.2022.2097460
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发表时间：
2022
期刊：
影响因子：
7.2
通讯作者：
R. Xiang
中科院分区：
文献类型：
--
作者：
Siyu Li;Shi;Baorui Tian;Na Li;Yanan Chen;Yanhua Liu;Weijun Su;Yan Fan;Yongjun Piao;Jia Li;Longlong Wang;Jin Zhao;Shu Wang;Yi Shi;R. Xiang
摘要：尽管在治疗多种类型的癌症方面取得了临床成功，但免疫检查点抑制剂（ICIs）在肿瘤突变负荷（TMB）和抗原性低的癌症中显示出有限的反应率。在这里，我们的目标是通过使用导致区域错误翻译和突变蛋白质的非蛋白氨基酸（NPA）来增强蛋白质翻译水平上的肿瘤抗原性。我们利用脯氨酸类似物氮杂环丁烷-2-羧酸（AZA），它可以通过脯氨酰-tRNA合成酶释放到脯氨酸tRNA中，导致在进行活性蛋白质合成的肿瘤细胞中产生一定比例的脯氨酸残基被Aze取代的突变蛋白质。为了在肿瘤细胞中特异性产生突变蛋白，使用抗 Cd44 抗体包被的脂质体纳米颗粒 (NP) 将 Aze 特异性递送到乳腺癌细胞中。 NPs递送的Aze可以与小鼠4T1同种异体肿瘤移植物中的蛋白质结合，从而激活细胞免疫反应，从而显着抑制4T1同种异体移植物的生长和肺转移，最终延长荷瘤小鼠的生存期。有趣的是，Aze 增加了 4T1 乳腺癌同种异体移植物对抗 PD1 抗体治疗的反应，表明 Aze 能够在肿瘤免疫治疗中使肿瘤对 ICI 治疗敏感。图解摘要
ABSTRACT Despite the clinical success in the treatment of several types of cancers, the immune checkpoint inhibitors (ICIs) show limited response rates in cancers with low tumor mutational burden (TMB) and antigenicity. Here, we aim to enhance tumor antigenicity at the protein translation level by using non-proteinogenic amino acids (NPAs) that cause regional mistranslation and mutated proteins. We utilized proline analogue azetidine-2-carboxylic acid (AZA), which can be discharged into proline tRNA by prolyl-tRNA synthetase, leading to the generation of a proportion of mutated proteins with proline residues substituted with Aze in tumor cells undergoing active protein synthesis. To specifically produce mutated proteins in tumor cells, the anti-Cd44 antibody-coated liposome nanoparticles (NPs) were used to deliver Aze specifically into the breast cancer cells. The Aze delivered by NPs can be incorporated into proteins in the 4T1 tumor allografts in mice, resulting in the activation of cellular immune responses and hence the significant inhibition of the growth of 4T1 allografts and the pulmonary metastasis, eventually prolonging the survival of tumor-bearing mice. Interestingly, Aze increases the response of 4T1 breast cancer allografts to anti-PD1 antibody treatment, suggesting Aze is able to sensitize tumors to the ICIs treatment in the immunotherapy of tumors. Graphical Abstract
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影响因子：
11.2
作者：
Duraiswamy J;Kaluza KM;Freeman GJ;Coukos G
通讯作者：
Coukos G
影响因子：
45.3
作者：
McDermott, David F.;Drake, Charles G.;Atkins, Michael B.
通讯作者：
Atkins, Michael B.
CD44的结构和功能。
DOI：
10.2741/a306
发表时间：
1998
期刊：
Frontiers in bioscience : a journal and virtual library
影响因子：
--
作者：
Lesley,J;Hyman,R
通讯作者：
Hyman,R
影响因子：
16.1
作者：
Bertrand, Nicolas;Wu, Jun;Xu, Xiaoyang;Kamaly, Nazila;Farokhzad, Omid C.
通讯作者：
Farokhzad, Omid C.
DOI：
10.1056/nejmoa1200690
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Topalian SL;Hodi FS;Brahmer JR;Gettinger SN;Smith DC;McDermott DF;Powderly JD;Carvajal RD;Sosman JA;Atkins MB;Leming PD;Spigel DR;Antonia SJ;Horn L;Drake CG;Pardoll DM;Chen L;Sharfman WH;Anders RA;Taube JM;McMiller TL;Xu H;Korman AJ;Jure-Kunkel M;Agrawal S;McDonald D;Kollia GD;Gupta A;Wigginton JM;Sznol M
通讯作者：
Sznol M