CELL INTELLIGENCE · 肿瘤细胞治疗研究

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 IFN 2 activates Cxcl9 expression to increase CTL tumor recruitment to suppress lung metastasis. METHODS: Codon usage-optimized IFN 2-encoding DNA was designed and cloned to plasmid. IFN 2-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 IFN 2 (LNP-mIFN 2), human IFN 2 plasmid, and mouse IFN 2 mRNA (LNP-mIFN 2-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 IFN 2-encoding plasmid and mRNA efficacy in IFN 2 expression and antitumor immunity, toxicity, and mechanism of action in vivo. RESULTS: LNP-encapsulated IFN 2-encoding plasmid primarily accumulated in tumor-bearing lungs in mice. LNP-IFN 2 therapy produces mouse IFN 2 protein in mouse tumor-bearing mice and human IFN 2 protein in human tumor-bearing humanized mice to suppress lung metastasis, respectively. Similarly, LNP-mIFN 2-mRNA therapy produces mouse IFN 2 protein and suppressed lung metastasis in tumor-bearing mice. The increased IFN 2 protein activates Cxcl9 expression and increases T cell infiltration in lung metastases. LNP-IFN 2 therapy did not induce liver toxicity and inflammatory cytokines. In human patients with cancer, IFN-I pathway activation is correlated with CXCL9 expression and T cell expansion after PD-(L)1 immune checkpoint inhibitor immunotherapy. Mechanistically, LNP-delivered IFN 2 suppresses tumor lung metastasis through upregulating Cxcl9 in tumor-bearing mice. CONCLUSIONS: Our findings determine that LNP-encapsulated IFN 2-encoding plasmid DNA and mRNA are effective agents in restoring IFN 2 expression to activate Cxcl9 expression to enhance T cell tumor recruitment to suppress tumor lung metastasis. LNP-IFN 2 is potentially a safe and yet effective third-generation IFN 2 agent for human cancer immunotherapy to treat patients with lung metastasis.