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JAK/STAT 依赖性嵌合抗原受体 (CAR) 表达:一种从双与门/或门设计中受益的设计,旨在提高特异性、减少肿瘤逃逸并影响肿瘤微环境。

JAK/STAT-Dependent Chimeric Antigen Receptor (CAR) Expression: A Design Benefiting From a Dual AND/OR Gate Aiming to Increase Specificity, Reduce Tumor Escape and Affect Tumor Microenvironment.

机构信息

School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

出版信息

Front Immunol. 2021 Jun 9;12:638639. doi: 10.3389/fimmu.2021.638639. eCollection 2021.


DOI:10.3389/fimmu.2021.638639
PMID:34177890
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8220211/
Abstract

Recent advances in cancer immunotherapy have attracted great interest due to the natural capacity of the immune system to fight cancer. This field has been revolutionized by the advent of chimeric antigen receptor (CAR) T cell therapy that is utilizing an antigen recognition domain to redirect patients' T cells to selectively attack cancer cells. CAR T cells are designed with antigen-binding moieties fused to signaling and co-stimulatory intracellular domains. Despite significant success in hematologic malignancies, CAR T cells encounter many obstacles for treating solid tumors due to tumor heterogeneity, treatment-associated toxicities, and immunosuppressive tumor microenvironment. Although the current strategies for enhancing CAR T cell efficacy and specificity are promising, they have their own limitations, making it necessary to develop new genetic engineering strategies. In this article, we have proposed a novel logic gate for recognizing tumor-associated antigens by employing intracellular JAK/STAT signaling pathway to enhance CAR T Cells potency and specificity. Moreover, this new-generation CAR T cell is empowered to secrete bispecific T cell engagers (BiTEs) against cancer-associated fibroblasts (CAFs) to diminish tumor metastasis and angiogenesis and increase T cell infiltration.

摘要

近年来,癌症免疫疗法的进展引起了极大的兴趣,因为免疫系统具有天然抵抗癌症的能力。嵌合抗原受体 (CAR) T 细胞疗法的出现彻底改变了这一领域,该疗法利用抗原识别结构域将患者的 T 细胞重新定向,以选择性攻击癌细胞。CAR T 细胞设计有抗原结合部分与信号和共刺激细胞内结构域融合。尽管在血液恶性肿瘤方面取得了显著成功,但由于肿瘤异质性、治疗相关毒性和免疫抑制肿瘤微环境,CAR T 细胞在治疗实体瘤方面遇到了许多障碍。尽管目前增强 CAR T 细胞功效和特异性的策略很有前景,但它们也有其自身的局限性,因此需要开发新的基因工程策略。在本文中,我们提出了一种通过利用细胞内 JAK/STAT 信号通路识别肿瘤相关抗原的新型逻辑门,以增强 CAR T 细胞的效力和特异性。此外,这种新一代的 CAR T 细胞能够分泌针对癌症相关成纤维细胞 (CAFs) 的双特异性 T 细胞衔接器 (BiTEs),以减少肿瘤转移和血管生成,并增加 T 细胞浸润。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/37554f6f8684/fimmu-12-638639-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/3e0f7f423752/fimmu-12-638639-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/cbf382cac1c3/fimmu-12-638639-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/5a27e5c43cab/fimmu-12-638639-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/5cb86dd100b2/fimmu-12-638639-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/652b586c661b/fimmu-12-638639-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/37554f6f8684/fimmu-12-638639-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/3e0f7f423752/fimmu-12-638639-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/cbf382cac1c3/fimmu-12-638639-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/5a27e5c43cab/fimmu-12-638639-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/5cb86dd100b2/fimmu-12-638639-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/652b586c661b/fimmu-12-638639-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ea/8220211/37554f6f8684/fimmu-12-638639-g006.jpg

相似文献

[1]
JAK/STAT-Dependent Chimeric Antigen Receptor (CAR) Expression: A Design Benefiting From a Dual AND/OR Gate Aiming to Increase Specificity, Reduce Tumor Escape and Affect Tumor Microenvironment.

Front Immunol. 2021

[2]
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Hepatobiliary Pancreat Dis Int. 2018-5-24

[3]
Making CAR T Cells a Solid Option for Solid Tumors.

Front Immunol. 2018-11-8

[4]
CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape.

Front Immunol. 2020

[5]
[Mechanisms of resistance and escape to CAR-T cells].

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[6]
Engineering CAR-T Cells for Next-Generation Cancer Therapy.

Cancer Cell. 2020-10-12

[7]
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Adv Cancer Res. 2024

[8]
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Semin Hematol. 2024-4

[9]
Improving the ability of CAR-T cells to hit solid tumors: Challenges and strategies.

Pharmacol Res. 2022-1

[10]
Current progress in chimeric antigen receptor T cell therapy for glioblastoma multiforme.

Cancer Med. 2021-8

引用本文的文献

[1]
Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T-cell therapy in solid tumors.

Cancer Sci. 2024-11

[2]
Engineering chimeric autoantibody receptor T cells for targeted B cell depletion in multiple sclerosis model: An study.

Heliyon. 2023-9-1

[3]
From barriers to novel strategies: smarter CAR T therapy hits hard to tumors.

Front Immunol. 2023

[4]
The Contribution of the Minimal Promoter Element to the Activity of Synthetic Promoters Mediating CAR Expression in the Tumor Microenvironment.

Int J Mol Sci. 2022-7-4

[5]
Application and Design of Switches Used in CAR.

Cells. 2022-6-13

本文引用的文献

[1]
Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide.

Sci Transl Med. 2021-1-6

[2]
The Impact of the Cancer Microenvironment on Macrophage Phenotypes.

Front Immunol. 2020

[3]
Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR.

Blood. 2020-9-17

[4]
Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells.

Cell Mol Immunol. 2020-6

[5]
Tunable self-cleaving ribozymes for modulating gene expression in eukaryotic systems.

PLoS One. 2020-4-30

[6]
Engineering of an enhanced synthetic Notch receptor by reducing ligand-independent activation.

Commun Biol. 2020-3-13

[7]
Target-Dependent Expression of IL12 by synNotch Receptor-Engineered NK92 Cells Increases the Antitumor Activities of CAR-T Cells.

Front Oncol. 2019-12-19

[8]
Genetically engineered T cells for cancer immunotherapy.

Signal Transduct Target Ther. 2019

[9]
Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy.

J Hematol Oncol. 2019-8-28

[10]
CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity.

Nat Biotechnol. 2019-7-22

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