肿瘤细胞治疗研究
英文原题：Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer.
这些结果表明，通过多重mRNA方法递送TME中通常缺失的细胞因子和抗原，可能为PDAC的有效免疫治疗铺平道路。
免疫治疗在胰腺导管腺癌（PDAC）中效果有限，原因在于其免疫排斥性肿瘤微环境（TME）缺乏自然杀伤（NK）细胞和T细胞应答所需的多种细胞因子。在此，我们设计了编码白细胞介素、趋化因子和干扰素的多重mRNA，作为一种安全有效的PDAC细胞因子疗法。瘤内注射IL-12、IL-18、CCL5、CXCL10和IFNβ mRNA可实现强效但短暂的细胞因子表达，从而在PDAC移植小鼠模型中激活NK细胞和CD8+ T细胞，并减少肿瘤生长和纤维化。将细胞因子与肿瘤抗原mRNA联合使用可增强树突状细胞抗原呈递以及局部和全身性CD8+ T细胞致敏，从而在单次给药后延长动物生存期。值得注意的是，纳米颗粒包裹细胞因子/抗原mRNA混合物可实现全身给药并局部递送至小鼠自体PDAC肿瘤，最终在50%的动物中产生治愈性应答，并维持抗原反应性T细胞持久存在。这些结果表明，采用多重mRNA方法递送TME中通常缺失的细胞因子和抗原，可能为PDAC的有效免疫治疗铺平道路。
Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses. Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC. Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8 + T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models. Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8 + T cell priming locally and systemically that prolongs animal survival after a single dose. Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence. These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC.
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