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RevCAR介导的针对表达PD-L1细胞的T细胞反应将抑制转化为激活。

RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation.

作者信息

Crespo Eugenia, Loureiro Liliana R, Stammberger Antonia, Hoffmann Lydia, Berndt Nicole, Hoffmann Anja, Dagostino Claudia, Soto Karla E G, Rupp Luise, Arndt Claudia, Schneider Martin, Ball Claudia R, Bachmann Michael, Schmitz Marc, Feldmann Anja

机构信息

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.

出版信息

NPJ Precis Oncol. 2025 Feb 9;9(1):42. doi: 10.1038/s41698-025-00828-6.


DOI:10.1038/s41698-025-00828-6
PMID:39924591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11808103/
Abstract

Applying CAR T-cell therapy to treat solid tumors is especially challenging due to the immunosuppressive tumor microenvironment (TME). While our modular RevCAR system enhances the safety and controllability of CAR T-cell therapy, effectively targeting solid tumors remains difficult. Since PD-L1 is an immune checkpoint frequently upregulated by cancer cells and their microenvironment, it is a relevant target for solid tumors. Here, we introduce a novel PD-L1 RevTM capable of redirecting RevCAR T-cells to specifically target and kill PD-L1-expressing tumor cells, becoming activated and secreting pro-inflammatory cytokines. This is shown in vitro with monolayer and 3D models, including patient-derived cultures, and in vivo. Furthermore, we demonstrate in vitro and in vivo an AND-gated targeting of cells simultaneously expressing PD-L1 and another tumor-associated antigen by the Dual RevCAR system. Our findings suggest that RevCAR-mediated targeting of PD-L1 could be a promising therapeutic approach for modulating the TME and improving solid tumor treatment.

摘要

由于免疫抑制性肿瘤微环境(TME),应用嵌合抗原受体(CAR)T细胞疗法治疗实体瘤尤其具有挑战性。虽然我们的模块化RevCAR系统提高了CAR T细胞疗法的安全性和可控性,但有效靶向实体瘤仍然困难。由于程序性死亡配体1(PD-L1)是一种经常被癌细胞及其微环境上调的免疫检查点,它是实体瘤的一个相关靶点。在此,我们引入了一种新型的PD-L1 RevTM,它能够重定向RevCAR T细胞,以特异性靶向并杀死表达PD-L1的肿瘤细胞,使其激活并分泌促炎细胞因子。这在体外的单层和三维模型(包括患者来源的培养物)以及体内得到了证实。此外,我们在体外和体内证明了双RevCAR系统对同时表达PD-L1和另一种肿瘤相关抗原的细胞的与门控靶向。我们的研究结果表明,RevCAR介导的对PD-L1的靶向可能是一种有前途的治疗方法,用于调节肿瘤微环境和改善实体瘤治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/76041cf7e106/41698_2025_828_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/68b3af4671c7/41698_2025_828_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/253bfc4648c3/41698_2025_828_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/ae0f4de33f8a/41698_2025_828_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/811f4623ad66/41698_2025_828_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/39fe829d61c2/41698_2025_828_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/8860e1474e3c/41698_2025_828_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/b3de0a895227/41698_2025_828_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/76041cf7e106/41698_2025_828_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/68b3af4671c7/41698_2025_828_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/253bfc4648c3/41698_2025_828_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/ae0f4de33f8a/41698_2025_828_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/811f4623ad66/41698_2025_828_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/39fe829d61c2/41698_2025_828_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/8860e1474e3c/41698_2025_828_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/b3de0a895227/41698_2025_828_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a4/11808103/76041cf7e106/41698_2025_828_Fig8_HTML.jpg

相似文献

[1]
RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation.

NPJ Precis Oncol. 2025-2-9

[2]
Specific and safe targeting of glioblastoma using switchable and logic-gated RevCAR T cells.

Front Immunol. 2023

[3]
Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells.

Front Immunol. 2023

[4]
Targeting PD-L1 in solid cancer with myeloid cells expressing a CAR-like immune receptor.

Front Immunol. 2024

[5]
RevCAR-expressing immune effector cells for targeting of Fn14-positive glioblastoma.

Cancer Gene Ther. 2024-9

[6]
Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1.

Mol Ther Oncol. 2024-10-5

[7]
Targeting Acute Myeloid Leukemia Using the RevCAR Platform: A Programmable, Switchable and Combinatorial Strategy.

Cancers (Basel). 2021-9-24

[8]
Oncolytic herpesvirus expressing PD-L1 BiTE for cancer therapy: exploiting tumor immune suppression as an opportunity for targeted immunotherapy.

J Immunother Cancer. 2021-3

[9]
Dual-function chimeric antigen receptor T cells targeting c-Met and PD-1 exhibit potent anti-tumor efficacy in solid tumors.

Invest New Drugs. 2021-2

[10]
Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer.

Mol Cancer. 2023-8-10

本文引用的文献

[1]
3D Models of Sarcomas: The Next-generation Tool for Personalized Medicine.

Phenomics. 2023-10-4

[2]
State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future?

Cells. 2024-4-23

[3]
T-Cell Lymphoma From CAR T-Cell Therapy-A New Safety Notice.

JAMA. 2024-2-6

[4]
Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells.

Front Immunol. 2023

[5]
Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment.

J Exp Clin Cancer Res. 2023-12-15

[6]
Specific and safe targeting of glioblastoma using switchable and logic-gated RevCAR T cells.

Front Immunol. 2023

[7]
Long-term outcomes following CAR T cell therapy: what we know so far.

Nat Rev Clin Oncol. 2023-6

[8]
CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances.

Mol Cancer. 2023-1-30

[9]
Immune Checkpoint Inhibitor Therapy in Oncology: Current Uses and Future Directions: State-of-the-Art Review.

JACC CardioOncol. 2022-12-20

[10]
Guidelines for visualization and analysis of DC in tissues using multiparameter fluorescence microscopy imaging methods.

Eur J Immunol. 2023-11

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