Targeting PLCG2 Suppresses Tumor Progression, Orchestrates the Tumor Immune Microenvironment and Potentiates Immune Checkpoint Blockade Therapy for Colorectal Cancer.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.98200
Xueliang Zhou, Joshua Lin, Yanfei Shao, Huang Zheng, Yi Yang, Shuchun Li, Xiaodong Fan, Hiju Hong, Zhihai Mao, Pei Xue, Sen Zhang, Jing Sun
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Abstract

Background: Tumor progression and limited benefits of immune checkpoint blockade (ICB) therapy have been two major challenges in the clinical management of colorectal cancer (CRC). The objective of our research was to explore the role of PLCG2 in CRC progression, tumor microenvironment, and potentiating ICB therapy. Methods: Based on bioinformatics analysis and a prospective clinical observational study, the expression, prognostic significance, and clinical relevance of PLCG2 in CRC were unveiled. The single-cell and spatial transcriptome revealed the role of PLCG2 in shaping the heterogeneity of the CRC tumor microenvironment. The biological function of PLCG2 was validated by in vivo and in vitro experiments. The underlying mechanisms were elucidated by RNA-seq, western blotting, qRT-PCR, and multicolor immunofluorescence. The multiplex immunohistochemistry and flow cytometry were adopted to clarify the immunomodulatory role of PLCG2 in facilitating CRC immune escape. The translational value of targeting PLCG2 to potentiate the efficacy of ICB therapy and synergistic therapy to improve prognosis was explored in the preclinical animal models. Results: In CRC, PLCG2 exhibited high expression levels and was strongly associated with poor prognosis and advanced clinicopathological characteristics of patients. The single-cell transcriptome shed light on its important role in cell communication and the development and differentiation of immune cells. The spatial transcriptome described the spatial distribution of PLCG2 in CRC tissues. Further mechanistic analysis demonstrated that PLCG2 could promote proliferation, invasion, metastasis, epithelial-mesenchymal transition, and cell cycle regulation and inhibit apoptosis of CRC cells via the Akt-mTOR pathway activation. Furthermore, PLCG2 was found to contribute greatly to the immunosuppressive microenvironment and enhanced immune escape as it significantly suppressed the infiltration and functional activation of CD8+ T cells and promoted the infiltration of Treg cells as well as PD-1 and PD-L1 expression. Meanwhile, knockdown of PLCG2 could potentiate the efficacy of ICB therapy. Conclusion: In summary, we have identified for the first time that PLCG2 could be considered a precise biomarker and promising therapeutic target for predicting CRC prognosis, optimizing individualized treatment, reversing CRC immune escape, and overcoming resistance to ICB therapy.

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靶向 PLCG2 可抑制肿瘤进展、协调肿瘤免疫微环境并增强结直肠癌免疫检查点阻断疗法的疗效。
背景:肿瘤进展和免疫检查点阻断疗法(ICB)疗效有限一直是结直肠癌(CRC)临床治疗的两大挑战。我们的研究旨在探索 PLCG2 在 CRC 进展、肿瘤微环境和 ICB 治疗中的作用。研究方法基于生物信息学分析和前瞻性临床观察研究,揭示了 PLCG2 在 CRC 中的表达、预后意义和临床相关性。单细胞和空间转录组揭示了 PLCG2 在形成 CRC 肿瘤微环境异质性中的作用。体内和体外实验验证了PLCG2的生物学功能。通过RNA-seq、Western印迹、qRT-PCR和多色免疫荧光阐明了其潜在机制。采用多重免疫组化和流式细胞术阐明了 PLCG2 在促进 CRC 免疫逃逸中的免疫调节作用。在临床前动物模型中探讨了靶向 PLCG2 的转化价值,以增强 ICB 治疗和协同治疗的疗效,改善预后。研究结果在 CRC 中,PLCG2 表现出高表达水平,并与患者的不良预后和晚期临床病理特征密切相关。单细胞转录组揭示了 PLCG2 在细胞通讯以及免疫细胞的发育和分化中的重要作用。空间转录组描述了 PLCG2 在 CRC 组织中的空间分布。进一步的机理分析表明,PLCG2可通过激活Akt-mTOR通路促进CRC细胞的增殖、侵袭、转移、上皮-间质转化和细胞周期调控,并抑制细胞凋亡。此外,研究还发现 PLCG2 能显著抑制 CD8+ T 细胞的浸润和功能活化,促进 Treg 细胞的浸润以及 PD-1 和 PD-L1 的表达,从而对免疫抑制性微环境和增强免疫逃逸起到重要作用。同时,敲除 PLCG2 可增强 ICB 治疗的疗效。结论综上所述,我们首次发现 PLCG2 可被视为预测 CRC 预后、优化个体化治疗、逆转 CRC 免疫逃逸和克服 ICB 治疗耐药性的精确生物标志物和有前景的治疗靶点。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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