肿瘤细胞治疗研究
英文原题：FcεRγI promotes canine CD8 chimeric antigen receptor T cell cytotoxicity through a Syk-NF-κB axis.
比较肿瘤学推动了癌症免疫治疗的发展，尽管调控犬类CAR-T 细胞（CART）治疗的细胞机制尚不清楚。
比较肿瘤学推动了癌症免疫治疗，尽管调控犬类CAR-T 细胞（CART）疗法的细胞机制仍知之甚少。在一项首次在犬类中开展的试验中，携带犬 4-1BB-CD3（cBB）结构域的抗 CD20 CART 诱导了 CD20 阴性淋巴瘤生长，但未能持续存在或清除 B 细胞。在此，我们表明，整合人 BB（hBB）的犬 CART 表现出更优的治疗功能，该功能由 FcεRI 介导。在重复杀伤试验和犬 B 细胞白血病异种移植模型中，hBB-CART 比 cBB-CART 显示出更强的细胞裂解和 CD8 T 细胞生长。转录谱分析显示，与 cBB-CART 相比，CD8 hBB-CART 中 FCER1G 和固有样基因上调。CRISPR 介导的 FCER1G 缺失和药理学 Syk/NF-κB 抑制表明，Syk-NF-κB 信号调节 FcεRI 介导的 hBB-CART 细胞毒性增强，并伴有颗粒酶 B 和 IFN-γ/TNF-α 产生增加。Syk-NF-κB 信号促进 hBB CART 中 FcεRI 表达，且 CAR-TCR 相互作用增强 NF-κB 信号，从而上调 FcεRI 并增强 CART 功能。这些研究确定了一个由 hBB 信号诱导的、具有强效治疗作用的固有样犬 CART 亚群，其有潜力改善犬和人类 CART 治疗。
Comparative oncology has advanced cancer immunotherapy, although cellular mechanisms governing chimeric antigen receptor T cell (CART) therapy in canines are poorly understood. In a first-in-canine trial, anti-CD20 CART with canine 4-1BB-CD3 (cBB ) domains induced CD20-negative lymphoma outgrowth but did not persist or deplete B cells. Here we show that canine CARTs incorporating human BB (hBB ) demonstrate superior therapeutic function, mediated by Fc R I. hBB -CART showed greater cytolysis and CD8 T cell outgrowth than cBB -CART in repetitive killing assays and a canine B cell leukemia xenograft model. Transcriptional profiling revealed upregulation of FCER1G and innate-like genes in CD8 hBB versus cBB -CARTs. CRISPR-mediated FCER1G deletion and pharmacologic Syk/NF- B inhibition indicated that Syk-NF- B signaling regulates Fc R I-mediated enhancement of hBB -CART cytotoxicity, associated with increased granzyme B and IFN- /TNF- production. Syk-NF- B signaling promotes Fc R I expression in hBB CARTs, and CAR-TCR interactions potentiate NF- B signaling to upregulate Fc R I and enhance CART function. These studies identify a potent therapeutic subset of innate-like canine CARTs induced by hBB signaling, which holds potential to improve both canine and human CART therapy.
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