Targeting Cbl-b by a small molecular inhibitor potentiates T cell receptor signaling and suggests rational combination strategies
文献类型：期刊论文
| 作者 | Li, Yuantong2; Tang, Haotian1,3; Shi, Wenhao3; Zhou, Yu3; Wen, Jiaxin3; Zhu, Jingwen3; Gao, Mingshan1; Xu, Tianfeng1; Xie, Hua1,2,3 |
| 刊名 | INTERNATIONAL IMMUNOPHARMACOLOGY
 |
| 出版日期 | 2026-01-15 |
| 卷号 | 169页码:15 |
| 关键词 | Cbl-b TCR signaling T cell activation MAPK pathway Combination therapy |
| ISSN号 | 1567-5769 |
| DOI | 10.1016/j.intimp.2025.116026 |
| 通讯作者 | Xie, Hua(hxie@simm.ac.cn) |
| 英文摘要 | Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, is a novel rising cancer immunotherapy target negatively regulating T cell response, yet the effects of its pharmacological inhibition on T cell activation remain unexplored. Here, we present a systematic pharmacological analysis of Cbl-b inhibition in T cells using a selective small-molecule Cbl-b inhibitor (Cbl-bi) which targets Cbl-b directly. Cbl-bi potentiates T-cell receptor (TCR) signaling in both Jurkat and primary murine T cells, as evidenced by increased phosphorylation of phospholipase C gamma 1 (PLC gamma 1) and extracellular signal-regulated kinase (Erk) and elevated interleukin-2 production following anti-CD3/CD28 stimulation. Transcriptomic profiling of Cbl-b-inhibited T cells revealed a pronounced activation and inflammatory signature, with enrichment of nuclear factor kB (NF-kappa B), mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Pharmacological interrogation of downstream signaling demonstrated that MAPK pathway activity is essential for the enhanced activation conferred by Cbl-b inhibition. Moreover, co-inhibition of autophagy or hematopoietic progenitor kinase 1 (HPK1) synergistically amplified the pro-activation effect of Cbl-b inhibition. Collectively, these findings provide mechanistic insight into Cbl-b's immunosuppressive role and identify rational combination strategies targeting Cbl-b, autophagy, or HPK1 to robustly potentiate T cell function for immunotherapy of cancer. |
| WOS关键词 | ACTIVATION ; PHOSPHORYLATION ; UBIQUITYLATION ; RESISTANCE ; REGULATOR ; AUTOPHAGY ; IMMUNITY ; INNATE |
| 资助项目 | Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0120231001] |
| WOS研究方向 | Immunology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001642220100001 |
| 出版者 | ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322369]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Xie, Hua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol & Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China 2.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China 3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Yuantong,Tang, Haotian,Shi, Wenhao,et al. Targeting Cbl-b by a small molecular inhibitor potentiates T cell receptor signaling and suggests rational combination strategies[J]. INTERNATIONAL IMMUNOPHARMACOLOGY,2026,169:15. |
| APA | Li, Yuantong.,Tang, Haotian.,Shi, Wenhao.,Zhou, Yu.,Wen, Jiaxin.,...&Xie, Hua.(2026).Targeting Cbl-b by a small molecular inhibitor potentiates T cell receptor signaling and suggests rational combination strategies.INTERNATIONAL IMMUNOPHARMACOLOGY,169,15. |
| MLA | Li, Yuantong,et al."Targeting Cbl-b by a small molecular inhibitor potentiates T cell receptor signaling and suggests rational combination strategies".INTERNATIONAL IMMUNOPHARMACOLOGY 169(2026):15. |
入库方式： OAI收割
来源：上海药物研究所
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