Cbl-b inhibitor NX-1607 activates MAPK/ERK signaling pathway and enhances T-cell activation
文献类型：期刊论文
| 作者 | Zhu, Wenting1,3; Lu, Shan1,3; Jia, Li1,3; Liu, Benjin1,3; Song, Shanshan3; Bao, Xubin3; Yu, Ting2; Zhang, Yongliang2; Miao, Zehong1,3; He, Jinxue1,3 |
| 刊名 | JOURNAL FOR IMMUNOTHERAPY OF CANCER
 |
| 出版日期 | 2025-05-29 |
| 卷号 | 13期号:5页码:18 |
| 关键词 | Tumor microenvironment - TME T cell Immunotherapy Immune modulatory Immune Checkpoint Inhibitor |
| DOI | 10.1136/jitc-2024-011180 |
| 英文摘要 | Backgroud: The E3 ubiquitin ligase casitas B lymphoma-b (Cbl-b) is pivotal in modulating immune responses by attenuating T-cell activation and cytokine production. Inhibiting Cbl-b presents a potential therapeutic strategy in immuno-oncology by enhancing immune activity. Methods: A rapid Homogeneous Time-Resolved Fluorescence (HTRF) assay was employed to evaluate the inhibitory efficacy of NX-1607 on Cbl-b. The effects of NX-1607 on T cell activation, cytokine production, and proliferation were characterized invitro using primary T cells and Jurkat T cells. A drug combination screening was performed utilizing the CD69 marker via flow cytometry to dentify signaling pathways involved in T cell activation by NX-1607. CRISPR/Cas9 technology was used to knock out PLCG1 and MAPK3/1 in Jurkat T cells, followed by the detection of p-PLC gamma 1 and p-ERK1/2 though Western blotting. The antitumor efficacy of NX-1607 was assessed in a murine model of A20 B-cell lymphoma using BALB/c mice, with subsequent flow cytometry analysis conducted to examine the phenotype of tumor-infiltrating lymphocytes (TILs). Results: Our data show that NX-1607 effectively inhibits Cbl-b activity at low nanomolar levels, boosting PLC gamma 1 and HCSL1 phosphorylation, activating MAPK/ERK signaling, and elevating CD69 expression. Inhibiting PLC gamma 1 and ERK1/2 significantly reduces NX-1607's effect on T-cell activation. Oral administration of NX-1607 notably decreases tumor growth in the A20 B-cell lymphoma model, with immunophenotyping analyses of tumor-infiltrating lymphocytes revealing increased CD3(+), CD4(+), and CD8(+) T cells in treated tumors. Furthermore, our results demonstrate that treatment with NX-1607 results in increased levels of phosphorylated PLC gamma 1 and ERK1/2 in circulating T cells. Conclusion: Taken together, these findings imply that the inhibition of Cbl-b by NX-1607 may enhance the activation of the MAPK/ERK signaling pathway, thereby sustaining T-cell activation. This provides compelling evidence for the molecular mechanism of NX-1607, underscoring the pivotal role of Cbl-b in controlling signal strength in T-cell activation after T-cell receptor (TCR) engagement. |
| WOS关键词 | E3 UBIQUITIN LIGASE ; PROTEOLYSIS |
| 资助项目 | National Natural Science Foundation of China[82073875] ; State Key Laboratory of Drug Research |
| WOS研究方向 | Oncology ; Immunology |
| 语种 | 英语 |
| WOS记录号 | WOS:001500054600001 |
| 出版者 | BMJ PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318234]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | He, Jinxue |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Wenting,Lu, Shan,Jia, Li,et al. Cbl-b inhibitor NX-1607 activates MAPK/ERK signaling pathway and enhances T-cell activation[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2025,13(5):18. |
| APA | Zhu, Wenting.,Lu, Shan.,Jia, Li.,Liu, Benjin.,Song, Shanshan.,...&He, Jinxue.(2025).Cbl-b inhibitor NX-1607 activates MAPK/ERK signaling pathway and enhances T-cell activation.JOURNAL FOR IMMUNOTHERAPY OF CANCER,13(5),18. |
| MLA | Zhu, Wenting,et al."Cbl-b inhibitor NX-1607 activates MAPK/ERK signaling pathway and enhances T-cell activation".JOURNAL FOR IMMUNOTHERAPY OF CANCER 13.5(2025):18. |
入库方式： OAI收割
来源：上海药物研究所
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