免疫抑制细胞在产生免疫抑制肿瘤微环境和促进肿瘤免疫逃逸中起重要作用。然而,其免疫抑制作用的分子机制尚不清楚.UBA3是神经前体细胞表达的发育下调蛋白8(NEDD8)激活酶E1的唯一催化亚基,在各种人类恶性肿瘤中高度表达,以及激活的Neddylation途径。在这项研究中,我们研究了UBA3依赖性neddylation途径与肺腺癌(LUAD)中几种免疫抑制细胞群浸润之间的关系.我们通过使用mRNA测序和功能富集分析探索了UBA3在LUAD细胞中的调控机制。通过蛋白质印迹法评估neddylation和免疫浸润之间的相关性,实时PCR,以及对公共数据库的分析。我们发现与邻近正常组织相比,LUAD组织中UBA3表达水平升高。阻断UBA3和neddylation途径促进了κ轻多肽基因增强子的磷酸化核因子在B细胞抑制剂(p-IκBα)中的积累,抑制肿瘤细胞来源的细胞因子的基因表达,例如C-C基序趋化因子配体(CCL)2,C-X-C基序配体(CXCL)1,CXCL2,集落刺激因子(CSF)1,CSF2白介素(IL)-6和IL-1B。此外,UBA3在LUAD细胞中的过表达与这些细胞因子的分泌有关,以及包括肿瘤相关巨噬细胞(TAMs)在内的免疫抑制细胞的募集和浸润,浆细胞样树突状细胞(pDC),Th2细胞和T调节细胞(Tregs)。这可以促进肿瘤免疫逃逸和LUAD的恶性进展。我们的发现为UBA3在通过调节核因子κB(NF-κB)信号和neddylation途径建立免疫抑制肿瘤微环境中的作用提供了新的见解。
Immunosuppressive cells play important roles in generating an immunosuppressive tumor microenvironment and facilitating tumor immune escape. However, the molecular mechanisms underlying their immunosuppressive effects remain unclear.
UBA3, the sole catalytic subunit of the neural precursor cell expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme E1, is highly expressed in various human malignancies, along with an activated neddylation pathway. In this study, we investigated the relationships between the
UBA3-dependent neddylation pathway and the infiltration of several immunosuppressive cell populations in lung adenocarcinoma (LUAD). We explored the regulatory mechanisms of UBA3 in LUAD cells by using mRNA sequencing and functional enrichment analyses. Correlations between neddylation and immune infiltrates were assessed by Western blotting, real-time PCR, and analyses of public databases. We found elevated levels of
UBA3 expression in LUAD tissues compared to adjacent normal tissues. Blocking
UBA3 and the neddylation pathway promoted the accumulation of the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (p-IκBα), inhibiting the gene expression of tumor cell-derived cytokines such as C-C motif chemokine ligand (CCL) 2, C-X-C motif ligand (CXCL)1, CXCL2, colony-stimulating factor (CSF) 1, CSF2 interleukin (IL)-6, and IL-1B. Moreover, the overexpression of
UBA3 in LUAD cells was associated with the secretion of these cytokines, and the recruitment and infiltration of immunosuppressive cells including tumor-associated macrophages (TAMs), plasmacytoid dendritic cells (pDCs), Th2 cells and T-regulatory cells (Tregs). This could facilitate the tumor immune escape and malignant progression of LUAD. Our findings provide new insights into the role of UBA3 in establishing an immunosuppressive tumor microenvironment by modulating nuclear factor kappa B (NF-кB) signaling and the neddylation pathway.