Assal Reem A, Elemam Noha M, Mekky Radwa Y, Attia Abdelrahman A, Soliman Aya Hesham, Gomaa Asmaa Ibrahim, Efthimiadou Eleni K, Braoudaki Maria, Fahmy Sherif Ashraf, Youness Rana A
Department of Pharmacology and Toxicology, Heliopolis University for Sustainable Development, Cairo-Ismailia Desert Road, 11785, Cairo, Egypt.
Clinical Sciences Department, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates.
Transl Oncol. 2024 Jul;45:101961. doi: 10.1016/j.tranon.2024.101961. Epub 2024 Apr 17.
Tumor microenvironment is an intricate web of stromal and immune cells creating an immune suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), Tumor microenvironment is a formidable barrier towards novel immune therapeutic approaches recently evading the oncology field. In this study, the main aim was to identify the intricate immune evasion tactics mediated by HCC cells and to study the epigenetic modulation of the immune checkpoints; Programmed death-1 (PD-1)/ Programmed death-Ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT)/Cluster of Differentiation 155 (CD155) at the tumor-immune synapse. Thus, liver tissues, PBMCs and sera were collected from Hepatitis C Virus (HCV), HCC as well as healthy individuals. Screening was performed to PD-L1/PD-1 and CD155/TIGIT axes in HCC patients. PDL1, CD155, PD-1 and TIGIT were found to be significantly upregulated in liver tissues and peripheral blood mononuclear cells (PBMCs) of HCC patients. An array of long non-coding RNAs (lncRNAs) and microRNAs validated to regulate such immune checkpoints were screened. The lncRNAs; CCAT-1, H19, and MALAT-1 were all significantly upregulated in the sera, PBMCs, and tissues of HCC patients as compared to HCV patients and healthy controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, and miR-30a-5p were downregulated in the sera and liver tissues of HCC patients. On the tumor cell side, knocking down of lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed the co-expression of PD-L1 and CD155 and accordingly induced the cytotoxicity of co-cultured primary immune cells. On the immune side, ectopic expression of the under-expressed microRNAs; miR-486-5p, miR-506-5p, and miR-30a-5p significantly decreased the transcript levels of PD-1 in PBMCs with no effect on TIGIT. On the other hand, ectopic expression of miR-944-5p and miR-105-5p in PBMCs dramatically reduced the co-expression of PD-1 and TIGIT. Finally, all studied miRNAs enhanced the cytotoxic effects of PBMCs against Huh7 cells. However, miR-105-5p showed the highest augmentation for PBMCs cytotoxicity against HCC cells. In conclusion, this study highlights a novel co-targeting strategy using miR-105-5p mimics, MALAT-1, CCAT-1 and H19 siRNAs to efficiently hampers the immune checkpoints; PD-L1/PD-1 and CD155/TIGIT immune evasion properties in HCC.
肿瘤微环境是由基质细胞和免疫细胞构成的复杂网络，在肿瘤周围形成免疫抑制屏障。在肝细胞癌（HCC）中，肿瘤微环境是近期肿瘤学领域新兴免疫治疗方法面临的巨大障碍。在本研究中，主要目的是确定HCC细胞介导的复杂免疫逃逸策略，并研究肿瘤免疫突触处免疫检查点程序性死亡蛋白1（PD - 1）/程序性死亡配体1（PD - L1）和具有Ig和ITIM结构域的T细胞免疫受体（TIGIT）/分化簇155（CD155）的表观遗传调控。因此，从丙型肝炎病毒（HCV）感染者、HCC患者以及健康个体中收集肝组织、外周血单个核细胞（PBMC）和血清。对HCC患者的PD - L1/PD - 1和CD155/TIGIT轴进行筛选。发现PDL1、CD155、PD - 1和TIGIT在HCC患者的肝组织和外周血单个核细胞（PBMC）中显著上调。筛选了一系列经证实可调节此类免疫检查点的长链非编码RNA（lncRNA）和微小RNA。与HCV患者和健康对照相比，lncRNA CCAT - 1、H19和MALAT - 1在HCC患者的血清、PBMC和组织中均显著上调。然而，miR - 944 - 5p、miR - 105 - 5p、miR - 486 - 5p、miR - 506 - 5p和miR - 30a - 5p在HCC患者的血清和肝组织中下调。在肿瘤细胞方面，敲低lncRNA CCAT - 1、MALAT - 1或H19可显著抑制PD - L1和CD155的共表达，并相应诱导共培养的原代免疫细胞的细胞毒性。在免疫方面，低表达的微小RNA miR - 486 - 5p、miR - 506 - 5p和miR - 30a - 5p的异位表达显著降低了PBMC中PD - 1的转录水平，而对TIGIT无影响。另一方面，PBMC中miR - 944 - 5p和miR - 105 - 5p的异位表达显著降低了PD - 1和TIGIT的共表达。最后，所有研究的微小RNA均增强了PBMC对Huh-7细胞的细胞毒性作用。然而，miR - 105 - 5p对PBMC对HCC细胞的细胞毒性增强作用最为显著。总之，本研究突出了一种新的联合靶向策略，即使用miR - 105 - 5p模拟物、MALAT - 1、CCAT - 1和H19 siRNA来有效阻碍HCC中免疫检查点PD - L1/PD - 1和CD155/TIGIT的免疫逃逸特性。
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