肿瘤细胞治疗研究
英文原题：RIG-I agonists promote antigen-spreading and facilitate durable CAR-T responses in pancreatic ductal adenocarcinoma.
RIG-I agonists promote antigen-spreading and facilitate durable CAR-T responses in pancreatic ductal adenocarcinoma.
瘤内 RIG-I 预激重编程 PDAC 肿瘤微环境，将无应答的肿瘤转变为允许 CAR-T 发挥作用的肿瘤，从而支持持久的多抗原免疫。
背景：胰腺导管腺癌（PDAC）总体上对嵌合抗原受体（CAR）T细胞疗法耐受。T细胞浸润不足、高度免疫抑制性微环境和抗原丢失，是CAR-T治疗面临的主要挑战。 方法：我们使用同系和人源异种移植PDAC模型，研究合成5′-三磷酸RNA（3p-RNA）与CAR-T细胞疗法的治疗协同作用。3p-RNA是细胞质双链RNA感受器视黄酸诱导基因I（RIG-I）的激动剂。通过流式细胞术、多重细胞因子检测、酶联免疫斑点（ELISpot）和疫苗—再激发实验，评估肿瘤生长、趋化因子分泌、免疫细胞组成、CAR-T细胞持久性及内源性T细胞应答。 结果：3p-RNA迅速诱导I型干扰素，同时促使趋化因子配体CCL5和CXCL9/10/11分泌，形成趋化梯度，将表达趋化因子受体CCR5⁺/CXCR3⁺的CAR-T细胞募集至肿瘤。RIG-I激活增强了CAR-T细胞增殖、活性和持久性。联合治疗使60%–70%的小鼠已形成肿瘤消退，而任一单药治疗基本无效。治愈小鼠可排斥CAR靶抗原阴性的肿瘤细胞再次攻击，证明发生了抗原扩展并产生内源性T细胞应答。 结论：瘤内RIG-I预激活可重编程PDAC微环境，将无应答肿瘤转化为有利于CAR-T细胞发挥作用的状态，促进持久、多抗原免疫。这些发现表明3p-RNA是一种可快速实施、具有临床可行性的联合治疗药物，有望将CAR-T疗效扩展至实体瘤。
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to chimeric antigen receptor (CAR)-T cell therapy. Insufficient T cell infiltration, a highly immunosuppressive microenvironment, and antigen loss pose major challenges for CAR-T cell therapy. METHODS: We investigated therapeutic synergies of synthetic 5'-triphosphate RNA (3p-RNA), an agonist of the cytoplasmic double-stranded RNA sensor Retinoic Acid Inducible Gene I (RIG-I), and CAR-T cell therapy using syngeneic and human xenograft PDAC models. Tumor growth, chemokine secretion, immune-cell composition, CAR-T persistence, and endogenous T cell responses were assessed by flow cytometry, multiplex cytokine arrays, Enzyme-linked Immunospot (ELISpot), and vaccination-challenge. RESULTS: 3p-RNA provoked rapid type I interferon accompanied with chemokine ligand CCL5 and CXCL9/10/11 secretion, creating chemokine gradients that recruited chemokine receptor CCR5 + /CXCR3 + CAR-T cells into tumors. RIG-I activation enhanced CAR-T cell proliferation, activity, and CAR-T persistence. Combination therapy eradicated established tumors in 60%-70% of mice, whereas either monotherapy was largely ineffective. Cured animals rejected CAR antigen-negative tumor cell rechallenge, demonstrating antigen-spreading and endogenous T cell responses. CONCLUSIONS: Intratumoral RIG-I priming reprograms the PDAC microenvironment, transforming a non-responsive cancer into a CAR-T-permissive one, supporting durable, poly-antigenic immunity. These findings position 3p-RNA as a rapid, clinically tractable co-therapy to extend CAR-T efficacy to solid tumors.
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