肿瘤细胞治疗研究
英文原题：Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control.
我们的研究强调，编码膜锚定细胞因子佐剂的下一代 mRNA 疫苗能够产生强效的效应 T 细胞，在降低毒性的同时提供有效的肿瘤控制。
传统mRNA癌症疫苗可以扩增肿瘤特异性CD8 T细胞的数量，但其效应功能可能受损。特定的细胞因子信号传导可能增强T细胞分化，从而实现更好的肿瘤杀伤。我们筛选了多种细胞因子，并鉴定出IL-12是mRNA疫苗的有效佐剂，但其具有显著的全身毒性。为了平衡疗效与毒性，我们开发了一种膜锚定IL-12（mtIL12）佐剂mRNA疫苗。该设计将mtIL12的表达限制在抗原呈递细胞表面，从而选择性激活抗原特异性T细胞，而不影响旁观者T细胞或NK细胞。mtIL12佐剂mRNA疫苗接种诱导了一种独特的前效应T细胞亚群，该亚群可产生高反应性效应T细胞，从而产生优越的抗肿瘤活性。此外，该方法克服了免疫检查点治疗耐药性并预防了癌症转移。我们的研究强调，编码膜锚定细胞因子佐剂的下一代mRNA疫苗可以产生强效效应T细胞，在降低毒性的同时提供有效的肿瘤控制。
Conventional mRNA cancer vaccines can expand the quantity of tumor-specific CD8 T cells, but their effector function might be compromised. Specific cytokine signaling may enhance T cell differentiation for better tumor killing. We screened various cytokines and identified IL-12 as a potent adjuvant for mRNA vaccines, though with significant systemic toxicity. To balance efficacy and toxicity, we developed a membrane-tethered IL-12 (mtIL12) adjuvant mRNA vaccine. This design restricts mtIL12 expression to the surface of antigen-presenting cells, thereby selectively activating antigen-specific T cells without affecting bystander T or NK cells. mtIL12 adjuvant mRNA vaccination induced a unique pre-effector T cell subset that gives rise to highly responsive effector T cells, resulting in superior anti-tumor activity. Moreover, this approach overcame immune checkpoint therapy resistance and prevented cancer metastasis. Our study highlights that next-generation mRNA vaccines encoding membrane-tethered cytokine adjuvants can generate potent effector T cells, offering effective tumor control with reduced toxicity.
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