Sun Yi, Qiu Xiaofen, Zhou Dalei, Ricciardi Sara, Shinohara Shuichi, Ma Jiangjun
Pediatric, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.
Transl Lung Cancer Res. 2024 Jul 30;13(7):1727-1741. doi: 10.21037/tlcr-24-505. Epub 2024 Jul 17.
The mechanism for memory T helper (Th) cell differentiation in malignant pleural effusion (MPE) of non-small cell lung cancer (NSCLC) is poorly understood. MicroRNAs (miRNAs), as small non-coding RNA that regulate gene expression, play a crucial role in the regulation of memory Th cell differentiation. However, whether miRNAs can inhibit the differentiation of memory Th cells in MPE of NSCLC has not been reported. This study aimed to explore miR-16-5p specifically inhibits interferon-gamma (IFN-γ)-regulated memory Th cell differentiation in MPE of NSCLC.
A total of 30 patients with NSCLC and 30 age- and sex-matched patients, who were clinically diagnosed as benign pleural effusion (BPE) of lung disease and had not received any intervention, were collected. The expression of nucleic acids, miRNAs, and cytokines was detected by polymerase chain reaction (PCR), miRNA microarray, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blotting.
The expression of CD4CD69 T cells in NSCLC with MPE was lower than that in lung disease BPE. CD4CD69 T cells highly express CD45RO and mainly secrete anti-tumor cytokines IFN-γ, interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α). The expression of miR-16-5p in CD4CD69 CD45RO T cells in MPE was higher than that in BPE. Moreover, miR-16-5p can bind to both IFN-γ promoter and its 5'untranslated region (5'-UTR), suggesting that - may be the target gene directly affected by miR-16-5p. IFN-γ also affects the differentiation of memory CD4 T cells by regulating T-bet.
We believe that miR-16-5p may regulate the decrease of differentiation of naïve CD4 T cells into memory CD4CD69 T cells through its target gene - in MPE, thus reducing the number of cytokines that produce anti-tumor effects. It may be the main reason for the low response rate of lung cancer with MPE immunotherapy.
非小细胞肺癌（NSCLC）恶性胸腔积液（MPE）中记忆性辅助性T（Th）细胞分化的机制尚不清楚。微小RNA（miRNA）作为调节基因表达的小型非编码RNA，在记忆性Th细胞分化的调节中起关键作用。然而，miRNA是否能抑制NSCLC-MPE中记忆性Th细胞的分化尚未见报道。本研究旨在探讨miR-16-5p特异性抑制NSCLC-MPE中干扰素-γ（IFN-γ）调节的记忆性Th细胞分化。
收集30例NSCLC患者及30例年龄、性别匹配的临床诊断为肺部疾病良性胸腔积液（BPE）且未接受任何干预的患者。通过聚合酶链反应（PCR）、miRNA微阵列、酶联免疫吸附测定（ELISA）、流式细胞术和蛋白质免疫印迹法检测核酸、miRNA和细胞因子的表达。
NSCLC-MPE中CD4CD69 T细胞的表达低于肺部疾病BPE。CD4CD69 T细胞高表达CD45RO，主要分泌抗肿瘤细胞因子IFN-γ、白细胞介素-2（IL-2）和肿瘤坏死因子-α（TNF-α）。MPE中CD4CD69 CD45RO T细胞中miR-16-5p的表达高于BPE。此外，miR-16-5p可与IFN-γ启动子及其5'非翻译区（5'-UTR）结合，提示IFN-γ可能是受miR-16-5p直接影响的靶基因。IFN-γ还通过调节T-bet影响记忆性CD4 T细胞的分化。
我们认为，miR-16-5p可能通过其靶基因IFN-γ调节MPE中初始CD4 T细胞向记忆性CD4CD69 T细胞分化的减少，从而减少产生抗肿瘤作用的细胞因子数量。这可能是NSCLC-MPE免疫治疗低反应率的主要原因。
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