ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3.
ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3.
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DOI：
10.1136/jitc-2023-007766
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发表时间：
2023-12-26
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
激活信号协整因子 3 (ASCC3) 已被确定为损害宿主免疫防御的致癌因子。然而，致癌的潜在机制及其对抗肿瘤免疫反应的影响仍不清楚。在本研究中，我们旨在探讨ASCC3在非小细胞肺癌（NSCLC）进展中的分子机制。分析了来自基因表达综合数据库的单细胞测序数据和来自癌症基因组图谱数据库的基因表达谱。探讨了 ASCC3 在 NSCLC 中的表达、临床相关性和生物学功能。然后，进行RNA测序、免疫沉淀、质谱、免疫荧光和流式细胞术分析，以探索潜在的分子机制。此外，在小鼠模型中进行了体内实验，以探讨敲低 ASCC3 以提高 NSCLC 中抗程序性死亡 1 (PD-1) 疗法疗效的可能性。 ASCC3 在 NSCLC 中显着上调，并与 NSCLC 患者不良的病理特征和预后相关。 ASCC3的过度表达促进NSCLC细胞的恶性表型并诱导免疫抑制肿瘤微环境，其特征是CD8+T细胞、自然杀伤细胞和树突状细胞减少，但调节性T（Treg）细胞增加。从机制上讲，ASCC3通过招募Cullin相关和neddylation dissociated 1 (CAND1)来稳定信号转导子和转录激活子(STAT)3信号，抑制泛素介导的STAT3降解，从而损害肿瘤细胞的I型干扰素反应，促进NSCLC的免疫抑制和进展。此外，ASCC3的高表达损害了抗PD-1疗法的功效，而抗PD-1抗体与ASCC3敲低相结合在临床前小鼠模型中发挥了有希望的协同功效。 ASCC3可以通过CAND1稳定STAT3通路，重塑肿瘤微环境并诱导对抗PD-1治疗的抵抗，从而促进NSCLC的进展。它是一个可靠的预后指标，可以作为非小细胞肺癌联合治疗的目标。
Activating signal cointegrator 3 (ASCC3) has been identified as an oncogenic factor that impairs host immune defense. However, the underlying mechanisms of carcinogenesis and its impact on the antitumor immune response remain unclear. In this study, we aimed to investigate the molecular mechanisms of ASCC3 in the progression of non-small cell lung cancer (NSCLC). Single-cell sequencing data from the Gene Expression Omnibus and gene expression profiles from The Cancer Genome Atlas database were analyzed. The expression, clinical relevance and biological functions of ASCC3 in NSCLC were explored. Then, RNA sequencing, immunoprecipitation, mass spectrometry, immunofluorescence, and flow cytometry analyses were conducted to explore the underlying molecular mechanisms. In addition, in vivo experiments in mouse models were conducted to explore the probability of ASCC3 knockdown to improve the efficacy of anti-Programmed Death-1 (PD-1) therapy in NSCLC. ASCC3 was significantly upregulated in NSCLC and correlated with poor pathological characteristics and prognosis in patients with NSCLC. Overexpression of ASCC3 promoted malignant phenotypes of NSCLC cells and induced an immunosuppressive tumor microenvironment, which was characterized by a decrease in CD8+ T cells, natural killer cells and dendritic cells but an increase in regulatory T(Treg) cells. Mechanistically, ASCC3 stabilized signal transducer and activator of transcription (STAT)3 signaling by recruiting Cullin-associated and neddylation dissociated 1 (CAND1), which inhibited ubiquitin-mediated degradation of STAT3, thereby impairing the type I interferon response of tumor cells and promoting the immunosuppression and progression of NSCLC. Furthermore, high expression of ASCC3 impaired the efficacy of anti-PD-1 therapy, and an anti-PD-1 antibody combined with ASCC3 knockdown exerted promising synergistic efficacy in a preclinical mouse model. ASCC3 could stabilize the STAT3 pathway via CAND1, reshaping the tumor microenvironment and inducing resistance to anti-PD-1 therapy, which promotes the progression of NSCLC. It is a reliable prognostic indicator and can be a target in combination therapy for NSCLC.
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