microRNA (miRNA) 是调节多个基因表达的小型非编码 RNA。 MiR-193a-3p 在许多癌症类型中发挥肿瘤抑制因子的作用，但其对诱导特异性抗肿瘤免疫反应的作用尚不清楚。因此，我们检查了脂质纳米颗粒 (LNP) 配制、化学修饰的合成 miR-193a-3p 模拟物 (INT-1B3) 对抗肿瘤免疫的影响。 INT-1B3 抑制远处肿瘤转移并显着延长生存期。即使没有表明长期免疫的治疗，INT-1B3治疗的动物也能完全免受自体肿瘤细胞的攻击。由于 T 细胞耗竭和过继性 T 细胞转移消除了肿瘤生长，对自体肿瘤细胞攻击的保护受到阻碍。用我们的 miR-193a-3p 模拟物 (1B3) 转染肿瘤细胞会导致肿瘤细胞死亡和凋亡，并伴有 DAMP 表达增加。 1B3转染的肿瘤细胞和未成熟DC的共培养导致DC成熟，并且这些成熟的DC能够刺激CD4和CD8 T细胞产生1型细胞因子。 CD4-CD8- T 细胞也产生 1 型细胞因子，甚至直接响应 1B3 转染的肿瘤细胞。活细胞成像证明 PBMC 介导的针对 1B3 转染肿瘤细胞的细胞毒性。这些数据首次证明 miR-193a-3p 通过调节肿瘤微环境和诱导免疫原性细胞死亡来诱导针对肿瘤发展的长期免疫。

microRNAs (miRNAs) are small, non-coding RNAs that regulate expression of multiple genes. MiR-193a-3p functions as a tumor suppressor in many cancer types, but its effect on inducing specific anti-tumor immune responses is unclear. Therefore, we examined the effect of our lipid nanoparticle (LNP) formulated, chemically modified, synthetic miR-193a-3p mimic (INT-1B3) on anti-tumor immunity. INT-1B3 inhibited distant tumor metastasis and significantly prolonged survival. INT-1B3-treated animals were fully protected against challenge with autologous tumor cells even in absence of treatment indicating long-term immunization. Protection against autologous tumor cell challenge was hampered upon T cell depletion and adoptive T cell transfer abrogated tumor growth. Transfection of tumor cells with our miR-193a-3p mimic (1B3) resulted in tumor cell death and apoptosis accompanied by increased expression of DAMPs. Co-culture of 1B3-transfected tumor cells and immature DC led to DC maturation and these mature DC were able to stimulate production of type 1 cytokines by CD4+ and CD8+ T cells. CD4-CD8- T cells also produced type 1 cytokines, even in response to 1B3-transfected tumor cells directly. Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death.