The use of immune checkpoint inhibitors that target programmed cell death‐1 (PD‐1) has been proposed for the treatment of advanced non‐small cell lung cancer (NSCLC). However, in clinical trials, cumulative response rates to anti‐PD‐1 treatment were approximately 20% in patients with NSCLC. CCR4‐NOT transcription complex, subunit 4 (CNOT4) is a RING finger protein with E3 ubiquitin ligase activity. We previously reported that CNOT4 may act as a tumor suppressor in NSCLC. Here, we examined whether CNOT4 can enhance the efficacy of anti‐PD‐1 immunotherapy in a model of NSCLC. The association of CNOT4 and overall survival was analyzed using datasets from The Cancer Genome Atlas (TCGA). Tumor models were established by subcutaneously implanting tumor cells line (A549 cell) into mice. CNOT4 was observed to be positively associated with relapse‐free survival and overall survival in patients with NSCLC. CNOT4 overexpression suppressed tumor growth in vivo and enhanced the effect of anti‐PD‐1 immunotherapy, which was accompanied by increased CD3⁺ and CD8⁺ T lymphocyte infiltration and higher interferon‐γ and tumor necrosis factor‐α levels. In conclusion, CNOT4 may enhance the efficacy of anti‐PD‐1 immunotherapy and may have potential as a prognostic marker for NSCLC, or as a combinational target with anti‐PD‐1 treatment for patients with NSCLC.

中文翻译：

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CNOT4增强抗PD-1免疫疗法在非小细胞肺癌模型中的疗效

已提议使用靶向程序性细胞死亡-1 (PD-1) 的免疫检查点抑制剂治疗晚期非小细胞肺癌 (NSCLC)。然而，在临床试验中，NSCLC 患者对抗 PD-1 治疗的累积反应率约为 20%。CCR4-NOT 转录复合物，亚基 4 (CNOT4) 是一种具有 E3 泛素连接酶活性的无名指蛋白。我们之前报道过 CNOT4 可能在 NSCLC 中充当肿瘤抑制因子。在这里，我们检查了 CNOT4 是否可以增强 NSCLC 模型中抗 PD-1 免疫疗法的疗效。使用来自癌症基因组图谱 (TCGA) 的数据集分析了 CNOT4 与总生存期的关联。通过将肿瘤细胞系（A549细胞）皮下植入小鼠体内建立肿瘤模型。观察到 CNOT4 与 NSCLC 患者的无复发生存期和总生存期呈正相关。CNOT4过表达抑制肿瘤生长体内并增强了抗 PD-1 免疫治疗的效果，伴随着 CD3 ⁺和 CD8 ⁺ T 淋巴细胞浸润增加以及干扰素-γ 和肿瘤坏死因子-α 水平升高。总之，CNOT4 可能会提高抗 PD-1 免疫疗法的疗效，并有可能作为 NSCLC 的预后标志物，或作为 NSCLC 患者的抗 PD-1 治疗的联合靶点。