肿瘤细胞治疗研究
英文原题：Single-chain IL-23 secretion by CAR-T cells improves tumor control and persistence against solid tumors.
嵌合抗原受体（CAR）-T 细胞疗法在血液系统恶性肿瘤中可实现持久缓解，但其在实体瘤中的成功部分受制于肿瘤高度免疫抑制的微环境。
嵌合抗原受体（CAR）T细胞疗法可使血液系统恶性肿瘤持久缓解，但由于实体瘤肿瘤微环境高度免疫抑制，对实体瘤的疗效仍受限制。第四代“增强型”CAR-T细胞经工程化改造，可分泌促炎分子以克服这一障碍。本研究构建靶向TnMUC1的CAR-T细胞，使其持续分泌单链白细胞介素12（scIL-12）或scIL-23。两种细胞因子增强型CAR-T均改善体外效应功能，与未增强的CAR-T相比，IFN-γ产生和细胞毒性增加。分泌scIL-12或scIL-23的CAR-T细胞在人体乳腺癌和前列腺癌小鼠异种移植模型中均显著延缓肿瘤生长并延长生存；其中scIL-23分泌可增强体内持久性，并使细胞保留于较早分化状态。这些发现提示，利用scIL-23增强CAR-T，是将CAR-T疗法拓展至实体瘤的有前景策略。
Chimeric antigen receptor (CAR)-T cell therapy achieves durable remissions in hematologic malignancies, yet its success against solid tumors is blunted in part by the tumors' highly immunosuppressive microenvironment. Fourth-generation "armored" CAR-T cells are engineered to secrete pro-inflammatory molecules to counteract this barrier. Here, we engineered TnMUC1-targeted CAR-T cells that constitutively secrete either single-chain interleukin-12 (scIL-12) or scIL-23. Both cytokine-armored CAR-T cell formats improved effector function in vitro, increasing interferon- production and cytotoxicity compared with their unarmored counterparts. scIL-12- and scIL23-secreting CAR-T cells significantly delayed tumor growth and prolonged survival in mouse xenograft models of human breast and prostate cancer, while scIL-23 secretion led to increases in in vivo persistence and retention of early differentiation states. These findings nominate scIL-23 armoring as a promising strategy to extend CAR-T cell therapy to solid tumors.
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