Department of Pathology, Xuzhou Central Hospital, No.29 Taihang Road, Xuzhou, 221004, China.
Prevention and Control Department, Xuzhou Oriental People's Hospital, Xuzhou, 221004, China.
Immunogenetics. 2023 Feb;75(1):17-25. doi: 10.1007/s00251-022-01275-4. Epub 2022 Sep 3.
Lung adenocarcinoma (LUAD) is the major type of lung cancer and is one of the deadliest cancers worldwide. IL4I1, as a gene associated with unsatisfactory prognosis, is involved in tumor immune escape, but its immune regulatory mechanism in LUAD is limited. Bioinformatics analysis was applied to analyze the differentially expressed mRNAs and enriched signaling pathways in LUAD tissue. Quantitative real-time polymerase chain reaction (qRT-PCR) was manipulated to test IL4I1 expression. We carried out several methods to examine cell functions: CCK-8 to measure LUAD cell proliferation; flow cytometry to determine cell apoptosis; Western blot to assess the expression of JAK/STAT pathway-related proteins and PD-L1; T cell cytotoxicity assay to evaluate the effect of IL4I1 on the immune escape of LUAD cells. Through bioinformatics analysis, IL4I1 was verified to be highly expressed in LUAD tissue, participate in the modulation of JAK/STAT signaling pathway, and be positively associated with CD274 (PD-L1) expression. Cell function experiments indicated that silencing IL4I1 notably repressed LUAD cell proliferation and induced apoptosis. IL4I1 silence would block JAK/STAT signaling pathway, but this effect could be reversed by RO8191 activator treatment. Moreover, IL4I1 silence suppressed PD-L1 expression and facilitated T cell cytotoxicity, while its inhibitory impact on PD-L1 expression and immune escape of LUAD cells could be reversed by atezolizumab treatment. Overall, we confirmed that IL4I1 promoted the malignant cell behaviors and immune escape of LUAD through JAK/STAT signaling pathway. IL4I1 has the potential to be a diagnostic biomarker for LUAD.
肺腺癌（LUAD）是肺癌的主要类型，也是全球最致命的癌症之一。IL4I1 作为与预后不佳相关的基因，参与肿瘤免疫逃逸，但它在 LUAD 中的免疫调节机制有限。本研究应用生物信息学分析方法分析 LUAD 组织中差异表达的 mRNAs 和富集的信号通路。采用实时定量聚合酶链反应（qRT-PCR）检测 IL4I1 的表达。通过几种方法检测细胞功能：CCK-8 法检测 LUAD 细胞增殖；流式细胞术检测细胞凋亡；Western blot 法检测 JAK/STAT 通路相关蛋白和 PD-L1 的表达；T 细胞细胞毒性测定法评估 IL4I1 对 LUAD 细胞免疫逃逸的影响。通过生物信息学分析，验证 IL4I1 在 LUAD 组织中高表达，参与 JAK/STAT 信号通路的调节，与 CD274（PD-L1）表达呈正相关。细胞功能实验表明，沉默 IL4I1 显著抑制 LUAD 细胞增殖并诱导细胞凋亡。IL4I1 沉默会阻断 JAK/STAT 信号通路，但用 RO8191 激活剂处理可逆转此作用。此外，IL4I1 沉默抑制 PD-L1 表达并促进 T 细胞细胞毒性，而其对 PD-L1 表达和 LUAD 细胞免疫逃逸的抑制作用可被 atezolizumab 治疗逆转。总之，我们证实 IL4I1 通过 JAK/STAT 信号通路促进 LUAD 恶性细胞行为和免疫逃逸。IL4I1 有望成为 LUAD 的诊断生物标志物。
