Concomitant inhibition of B7-H3 and PD-L1 expression by a novel and synthetic microRNA delivers potent antitumor activities in colorectal tumor models

• Published in: Investigational new drugs 2021-10, Vol.39 (5), p.1267-1274
• Main Authors: Meng, Fanyi, Chen, Yinshuang, Yang, Man, Zhang, Hongjian, Wang, Weipeng
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; B7 Antigens - antagonists & inhibitors; B7-H1 Antigen - antagonists & inhibitors; Bevacizumab; Bevacizumab - therapeutic use; Biomarkers, Tumor; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - pathology; Gene regulation; Humans; Immunotherapy; Male; Medicine; Medicine & Public Health; Mice; Mice, SCID; MicroRNAs; MicroRNAs - pharmacology; miRNA; Nucleotides; Oncology; PD-L1 protein; Pharmacology/Toxicology; Phenylurea Compounds - therapeutic use; Preclinical Studies; Pyridines - therapeutic use; Ribonucleic acid; RNA; Synergistic effect; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-021-01123-4

Summary The families of miR-34 and miR-449 share the same seed region. However, the members showed differential effects on the expression of B7-H3 and PD-L1 in HCT-116 cells. Using miR-34a as a template, the non-seed region was modified by nucleotide alteration, yielding four synthetic microRNA (miRNA) analogs. Among those, NS-MX3, with a base alteration from G to C at the 18th locus of miR-34a, showed the most potent inhibition on both B7-H3 and PD-L1 expression. Subsequent investigations demonstrated that NS-MX3 had a broad anti-proliferation activity against several colorectal tumor cell lines and its antitumor effect was consistently reflected by tumor growth inhibition (TGI) in the HCT-116 xenograft model. In addition, NS-MX3 displayed a synergistic effect on TGI when combined with bevacizumab or regorafenib. Further analysis revealed that the superior antitumor activity of NS-MX3 was correlated to concomitant suppression of both B7-H3 and PD-L1 expression in tumor tissues. Taken together, the present study indicates that the non-seed region of miRNAs plays an important role in the regulation of checkpoint genes, thus showcasing single nucleotide alteration of the non-seed region as a promising approach to discover and develop novel immunotherapies.