Lipid nanoparticle-delivered IFNα2 activates Cxcl9 to increase T cell tumor recruitment to suppress lung metastasis

作者：K. R. Fick, Nicholas Kerns, Yang Zhao, Zainab Tiamiyu, Dakota B. Poschel, Patrick Czabala, Dafeng Yang, Yi Tang, Jin Xie, Valentyna I. Fesenkova, Rafał Pacholczyk, Huidong Shi, Kebin Liu, Priscilla S. Redd · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-011415 · 被引用次数：6 · 研究领域：Immune cells in cancer、interferon and immune responses、Cancer Immunotherapy and Biomarkers

BACKGROUND: Emerging clinical and mouse tumor data indicate that tumor cells induce immune suppression in an anatomical site-specific manner. In lung metastases, tumor cell programmed death-ligand 1 (PD-L1) engages myeloid cell programmed cell death protein 1 to activate SHP2 to suppress type I interferon (IFN-I) expression to repress Cxcl9 expression to impair cytotoxic T lymphocyte (CTL) tumor recruitment. Loss of IFN-I expression thus underlies tumor immune evasion in lung metastases niche. We aimed at testing the hypothesis that forcing tumor cells to express IFNα2 activates Cxcl9 expression to increase CTL tumor recruitment to suppress lung metastasis. METHODS: Codon usage-optimized IFNα2-encoding DNA was designed and cloned to plasmid. IFNα2-encoding messenger RNA (mRNA) was synthesized. The plasmid DNA and mRNA were encapsulated into DOTAP (N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate)-cholesterol to generate lipid nanoparticle (LNP)-encapsulated mouse IFNα2 (LNP-mIFNα2), human IFNα2 plasmid, and mouse IFNα2 mRNA (LNP-mIFNα2-mRNA). Mouse breast tumor spontaneous lung metastasis, mouse melanoma experimental lung metastasis, and human colon tumor experimental lung metastasis humanized mouse models were used to determine LNP-encapsulated IFNα2-encoding plasmid and mRNA efficacy in IFNα2 expression and antitumor immunity, toxicity, and mechanism of action in vivo. RESULTS: LNP-encapsulated IFNα2-encoding plasmid primarily accumulated in tumor-bearin...