E3 连接酶 TRIM28 通过增强髓系来源抑制细胞的募集促进非小细胞肺癌对 PD-1 抑制剂的耐药性。
E3 ligase TRIM28 promotes anti-PD-1 resistance in non-small cell lung cancer by enhancing the recruitment of myeloid-derived suppressor cells.
机构信息
Department of Internal Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, Anhui, China.
Department of Respiratory Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, 2 Zheshan West Road, Wuhu, 241000, Anhui, China.
出版信息
J Exp Clin Cancer Res. 2023 Oct 21;42(1):275. doi: 10.1186/s13046-023-02862-3.
BACKGROUND
Alterations in several tripartite motif-containing (TRIM) family proteins have been implicated in the pathogenesis of lung cancer. TRIM28, a member of the TRIM E3 ligase family, has been associated with tumorigenesis, cell proliferation, and inflammation. However, little is known about TRIM28 expression and its role in the immune microenvironment of non-small cell lung cancer (NSCLC).
METHODS
We assessed the clinical significance of TRIM28 in tissue microarrays and TCGA cohorts. We investigated the function of TRIM28 in syngeneic mouse tumor models, the Kras; Tp53 (KP) mouse model, and humanized mice. Immune cell composition was analyzed using flow cytometry and immunohistochemistry.
RESULTS
Our findings revealed a positive correlation between TRIM28 expression and the infiltration of suppressive myeloid-derived suppressor cells (MDSCs) in NSCLC. Moreover, silencing TRIM28 enhanced the efficacy of anti-PD-1 immunotherapy by reshaping the inflamed tumor microenvironment. Mechanistically, we demonstrated that TRIM28 could physically interact with receptor-interacting protein kinase 1 (RIPK1) and promote K63-linked ubiquitination of RIPK1, which is crucial for sustaining activation of the NF-κB pathway. Mutagenesis of the E3 ligase domain corroborated the essential role of E3 ligase activity in TRIM28-mediated NF-κB activation. Further experiments revealed that TRIM28 could upregulate the expression of CXCL1 by activating NF-κB signaling. CXCL1 could bind to CXCR2 on MDSCs and promote their migration to the tumor microenvironment. TRIM28 knockdown increased responsiveness to anti-PD-1 therapy in immunocompetent mice, characterized by increased CD8T tumor-infiltrating lymphocytes and decreased MDSCs.
CONCLUSION
The present study identified TRIM28 as a promoter of chemokine-driven recruitment of MDSCs through RIPK1-mediated NF-κB activation, leading to the suppression of infiltrating activated CD8T cells and the development of anti-PD-1 resistance. Understanding the regulation of MDSC recruitment and function by TRIM28 provides crucial insights into the association between TRIM28 signaling and the development of an immunosuppressive tumor microenvironment. These insights may inform the development of combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in NSCLC.
背景
几种三部分基序（TRIM）家族蛋白的改变与肺癌的发病机制有关。TRIM28 是 TRIM E3 连接酶家族的成员，与肿瘤发生、细胞增殖和炎症有关。然而，关于 TRIM28 在非小细胞肺癌（NSCLC）免疫微环境中的表达及其作用知之甚少。
方法
我们评估了 TRIM28 在组织微阵列和 TCGA 队列中的临床意义。我们在同基因小鼠肿瘤模型、Kras；Tp53（KP）小鼠模型和人源化小鼠中研究了 TRIM28 的功能。使用流式细胞术和免疫组织化学分析免疫细胞组成。
结果
我们的研究结果表明，TRIM28 表达与 NSCLC 中抑制性髓样来源抑制细胞（MDSC）的浸润呈正相关。此外，沉默 TRIM28 通过重塑炎症肿瘤微环境增强了抗 PD-1 免疫治疗的疗效。在机制上，我们证明 TRIM28 可以与受体相互作用蛋白激酶 1（RIPK1）物理相互作用，并促进 RIPK1 的 K63 连接泛素化，这对于维持 NF-κB 途径的激活至关重要。E3 连接酶结构域的突变证实了 E3 连接酶活性在 TRIM28 介导的 NF-κB 激活中的重要作用。进一步的实验表明，TRIM28 通过激活 NF-κB 信号通路上调 CXCL1 的表达。CXCL1 可以与 MDSC 上的 CXCR2 结合，并促进其向肿瘤微环境迁移。TRIM28 敲低增加了免疫活性小鼠对抗 PD-1 治疗的反应性，表现为 CD8T 肿瘤浸润淋巴细胞增加，MDSC 减少。
结论
本研究鉴定了 TRIM28 通过 RIPK1 介导的 NF-κB 激活促进趋化因子驱动的 MDSC 募集，导致浸润的激活 CD8T 细胞减少和抗 PD-1 耐药的发展。了解 TRIM28 对 MDSC 募集和功能的调节提供了关于 TRIM28 信号与免疫抑制性肿瘤微环境发展之间关联的重要见解。这些见解可能为增强 NSCLC 免疫检查点阻断治疗的有效性的联合治疗提供信息。
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