免疫抑制细胞在产生免疫抑制的肿瘤微环境和促进肿瘤免疫逃逸中起着重要作用。然而，它们的免疫抑制效应的分子机制仍不清楚。UBA3是神经前体细胞表达发育下调蛋白8（NEDD8）激活酶E1的唯一催化亚基，在各种人类恶性肿瘤中高表达，并伴有激活的Nedd化途径。在本研究中，我们研究了UBA3依赖的Nedd化途径与肺腺癌（LUAD）中几种免疫抑制细胞群体的浸润之间的关系。我们通过mRNA测序和功能富集分析探索了UBA3在LUAD细胞中的调节机制。通过蛋白质印迹、实时PCR和公共数据库的分析评估了Nedd化与免疫浸润之间的相关性。我们发现，与癌旁正常组织相比，LUAD组织中UBA3的表达水平升高。阻断UBA3和Nedd化途径能促进磷酸化的kappa轻链偶联因子增强子（p-IκBα）的积累，抑制肿瘤细胞源性细胞因子如C-C motif化学因子配体（CCL）2、C-X-C motif配体（CXCL）1、CXCL2、集落刺激因子（CSF）1、CSF2、白细胞介素（IL）-6和IL-1B的基因表达。此外，LUAD细胞中UBA3的过表达与这些细胞因子的分泌，以及肿瘤相关巨噬细胞（TAMs）、浆细胞样树突状细胞（pDCs）、Th2细胞和调节性T细胞（Tregs）的招募和浸润相关。这可能促进LUAD的肿瘤免疫逃逸和恶性进展。我们的研究结果为UBA3在调节核因子kappa B（NF-кB）信号转导和Nedd化途径中建立免疫抑制性肿瘤微环境的作用提供了新的见解。© 2023. 作者。

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.© 2023. The Author(s).