TBX3形成免疫抑制微环境并诱导免疫治疗耐药。

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-01-06 eCollection Date: 2025-01-01 DOI:10.7150/thno.103175
Zhi Liu, Chunyu Zhang, Jiatong Xiao, Yunbo He, Haisu Liang, Jinliang Huang, Zhiyong Cai, Zhenglin Yi, Mingfeng Chen, Yixiao Li, Jun Zhang, Fenglian Liu, Peng Ren, Huihuang Li, Jinbo Chen, Benyi Fan, Jiao Hu, Xiongbing Zu, Dingshan Deng
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引用次数: 0

摘要

背景:确定预测免疫治疗疗效的生物标志物和发现联合治疗的新靶点是改善膀胱癌(BLCA)患者预后的关键因素。方法:首先,利用多个公共数据库的数据,探讨TBX3在正常组织和泛癌组织中的表达模式,以及TBX3与免疫微环境的相关性。然后,我们结合大量RNA测序、单细胞RNA测序、高通量细胞因子阵列、功能实验、ProcartaPlex多重免疫分析和TissueFAXS全景组织定量分析等多种技术,证明TBX3在BLCA中形成免疫抑制肿瘤微环境(TME)。结果:通过系统的多组学分析,我们确定TBX3是与BLCA免疫抑制微环境相关的关键因素。我们发现TBX3主要在恶性细胞中表达,TBX3高水平的肿瘤细胞增加tgf - β1的分泌,促进癌相关成纤维细胞(cancer-associated fibroblasts, CAFs)的浸润,从而形成免疫抑制微环境。我们进一步证明TBX3通过结合tgf - β1启动子增强tgf - β1的表达,阻断tgf - β1可抵消TBX3的免疫抑制作用。TBX3通过降低GZMB+ CD8+ T细胞的比例,降低了CD8+ T细胞的杀伤效率,并且TBX3与抗pd -1治疗联合增加了体内CD8+ T细胞的浸润,降低了体内CAFs。我们还验证了组织微阵列中TBX3+恶性细胞与CD8+ T细胞呈负相关,与cas呈正相关。最后,我们发现TBX3在我们的真实免疫治疗队列和多个公共队列中预测免疫治疗疗效。结论:TBX3通过诱导免疫抑制微环境促进BLCA的进展和免疫治疗耐药,靶向TBX3可提高BLCA免疫治疗的疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance.

Background: Identifying biomarkers that predict immunotherapy efficacy and discovering new targets for combination therapies are critical elements for improving the prognosis of bladder cancer (BLCA) patients. Methods: Firstly, we explored the expression patterns of TBX3 in normal and pan-cancer tissues and the correlation between TBX3 and the immune microenvironment using data from multiple public databases. Then, we combined various techniques, including bulk RNA sequencing, single-cell RNA sequencing, high-throughput cytokine arrays, functional experiments, ProcartaPlex multiplex immunoassays and TissueFAXS panoramic tissue quantification assays, to demonstrate that TBX3 shapes an immunosuppressive tumor microenvironment (TME) in BLCA. Results: We identified TBX3 as a key factor associated with the immunosuppressive microenvironment in BLCA through a systematic multi-omics analysis. We found that TBX3 is primarily expressed in malignant cells, where TBX3high tumor cells increase the secretion of TGFβ1, which promotes the infiltration of cancer-associated fibroblasts (CAFs), thereby forming an immunosuppressive microenvironment. We further demonstrated that TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter, and blocking TGFβ1 counteracts the immunosuppressive effects of TBX3. Moreover, TBX3 reduced the cancer-killing efficiency of CD8+ T cells by decreasing the proportion of GZMB+ CD8+ T cells, and knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration and reduced CAFs in vivo. We also validated the inverse relationship between TBX3+ malignant cells and CD8+ T cells and the positive relationship with CAFs in tissue microarrays. Lastly, we found that TBX3 predicted immunotherapy efficacy in our real-world immunotherapy cohort and multiple public cohorts. Conclusion: In summary, TBX3 promotes BLCA progression and immunotherapy resistance by inducing an immunosuppressive microenvironment, and targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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