PO.IM01.02 · 免疫学

靶向USP22重编程肿瘤微环境并使KRAS突变、TP53缺失型肺癌对免疫治疗敏感

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS-mutant, TP53-Null Lung cancer to immunotherapy

编号 2909 展板 19 时间 4/20 02:00–05:00 区域 Section 10 主讲 Keqiang Zhang, PhD

分会场 Modifiers of Inflammation and the Tumor Microenvironment

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作者与单位 Authors & Affiliations

Keqiang Zhang, Ching Ouyang, jinhui Wang, Wendong Li, Walter Tsark, Yuanyuan Gao, Mingxiao Yang, Aimin Li, Colt Egelston, Crystal Marconett, Dan Raz

City of Hope National Medical Center, Duarte, CA

摘要 Abstract

中文摘要

泛素特异性肽酶22（USP22）是一种去泛素化酶，也是“癌症致死”基因特征谱的组成部分，在许多癌症中过表达，并与复发、治疗耐药和不良预后相关。尽管USP22近来被认为参与肿瘤免疫逃逸，但其在KRAS驱动的肺癌及抗肿瘤免疫中的作用仍不清楚。在此，我们旨在探究USP22在KRAS驱动的肺癌中对肿瘤进展和抗肿瘤免疫的作用。通过免疫组织化学分析发现，USP22在几乎所有人类KRAS突变型肺腺癌以及早期KRAS诱导的小鼠肿瘤中高表达，其与增殖标志物Ki67的强相关性凸显了USP22作为KRAS驱动肿瘤生物学的一个潜在重要介导因子，并强化了其作为治疗靶点的前景。为界定USP22在肿瘤进展和免疫调节中的作用，我们在KRAS G12D；Tp53-/-（KP）小鼠中构建了条件性Usp22基因敲除（Usp22-KO）模型。Usp22缺失显著抑制了肿瘤生长、延长了生存期并促进了肿瘤分化，同时伴随KRAS通路活性降低和p53信号的部分恢复。空间转录组学、RNA测序和多重免疫荧光显示，Usp22缺失通过减少CD206+ M2巨噬细胞、降低TGF-beta1水平、限制血管生成、增加CD8+ T细胞浸润以及减少FOXP3+调节性T细胞，重编程了肿瘤微环境。在机制上，Usp22-KO改变了基因表达和蛋白稳定性，降低了c-Myc、PD-L1、TGF-beta1和富含半胱氨酸的酸性分泌蛋白（SPARC）；TGF-beta1-SPARC轴的破坏导致免疫抑制性PD-L1^+ M2巨噬细胞的显著耗竭。在功能上，Usp22缺失大幅增强了KP肺癌对抗PD-L1免疫检查点阻断的敏感性。总之，这些发现揭示USP22是KRAS突变、TP53缺失型肺癌中肿瘤进展和免疫抑制的关键驱动因素，并证明靶向USP22对于克服免疫检查点抑制剂治疗耐药具有重要的治疗潜力。

查看英文原文 English abstract

Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the “Death-By-Cancer” gene signature, is overexpressed in many cancers and associated with recurrence, therapy resistance, and poor prognosis. Although USP22 has recently been implicated in tumor immune evasion, its role in KRAS-driven lung cancer and antitumor immunity has remained unclear. Here, we aimed to investigate the role of USP22 in tumor progression and antitumor immunity in KRAS-driven lung cancer. By immunohistochemistry analysis, USP22 was found to be highly expressed in nearly all human KRAS-mutant lung adenocarcinomas and in early-stage KRAS-induced mouse tumors, where its strong correlation with the proliferation marker Ki67 highlights USP22 as a potentially important mediator of KRAS-driven tumor biology and reinforces its promise as a therapeutic target. To define USP22's role in tumor progression and immune regulation, we generated a conditional Usp22 knockout (Usp22-KO) model in KRAS G12D ; Tp53 -/- (KP) mice. Usp22 loss significantly suppressed tumor growth, prolonged survival, and promoted tumor differentiation, accompanied by reduced KRAS pathway activity and partial restoration of p53 signaling. Spatial transcriptomics, RNA sequencing, and multiplex immunofluorescence revealed that Usp22 deletion reprogrammed the tumor microenvironment by decreasing CD206 + M2 macrophages, reducing TGF-beta1 levels, limiting angiogenesis, increasing CD8 + T cell infiltration, and diminishing FOXP3 + regulatory T cells. Mechanistically, Usp22-KO altered gene expression and protein stability, reducing c-Myc, PD-L1, TGF-beta1, and secreted protein acidic and rich in cysteine (SPARC); disruption of the TGF-beta1-SPARC axis led to a marked depletion of immunosuppressive PD-L1^+ M2 macrophages. Functionally, Usp22 deletion substantially enhanced sensitivity to anti-PD-L1 immune checkpoint blockade in KP lung cancer. Collectively, these findings reveal USP22 as a critical driver of tumor progression and immunosuppression in KRAS-mutant, TP53-deficient lung cancer and demonstrate that targeting USP22 has significant therapeutic potential for overcoming resistance to immune checkpoint inhibitor therapy.

利益披露 Disclosure

K. Zhang, None.. C. Ouyang, None.. J. Wang, None.. W. Li, None.. W. Tsark, None.. Y. Gao, None.. M. Yang, None.. A. Li, None.. C. Egelston, None.. C. Marconett, None.. D. Raz, None.

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