CD318 is a target of chimeric antigen receptor T cells for the treatment of colorectal cancer
CD318 is a target of chimeric antigen receptor T cells for the treatment of colorectal cancer
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DOI：
10.1007/s10238-022-00967-1
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发表时间：
2022-12
影响因子：
4.6
通讯作者：
Ming Li;Shanglin Li;R. Zhao;Jiang Lv;Diwei Zheng;L. Qin;Siyu Li;Qiting Wu;Youguo Long;Zhaoyang Tang;Yanlai Tang;Lihua Yang;Yao Yao-Yao;Xuequn Luo;Peng Li
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文献类型：
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作者：
Ming Li;Shanglin Li;R. Zhao;Jiang Lv;Diwei Zheng;L. Qin;Siyu Li;Qiting Wu;Youguo Long;Zhaoyang Tang;Yanlai Tang;Lihua Yang;Yao Yao-Yao;Xuequn Luo;Peng Li
结直肠癌（CRC）目前预后不良，中位生存期为6.9年;为了缓解这种恶性癌症，我们提出建立CRC异种移植物，可用于评估过继嵌合抗原受体（CAR）-T细胞的细胞毒性，并加速CAR-T细胞的临床转化，用于对抗CRC。我们首先基于数百个临床样本验证了CD 318在原发性人CRC组织中的表达水平高于正常组织。然后，我们重定向了含有抗CD 318单链可变片段（抗CD 318 scFv）、CD 3 γ、CD 28和Toll样受体2（TLR 2）结构域的CAR-T细胞。接下来，我们在体外评估了这些CAR-T细胞在遇到CD 318 + CRC细胞时的表面表型变化、细胞毒性和细胞因子分泌方面的功能。最后，我们建立了两种不同的异种移植小鼠模型，以评估体内抗肿瘤活性。结果表明，CAR 318 T细胞在体外被显著活化，并对CRC细胞表现出较强的细胞毒性和分泌精氨酸的能力。此外，与CAR 19 T细胞相比，CAR 318 T细胞在不同的异种移植小鼠模型中诱导CRC消退并抑制肿瘤。总之，我们的工作表明CAR 318 T细胞具有强大的抗肿瘤能力，代表了CRC的一种有前途的治疗方法。
Colorectal cancer (CRC) currently has a poor prognosis with a 6.9-year median survival time; to relieve this malignant cancer, we proposed to establish CRC xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR)-T cells and accelerate the clinical translation of CAR-T cells for use against CRC. We first verified that CD318 had a higher expression level in primary human CRC tissues than in normal tissues based on hundreds of clinical samples. Then, we redirected CAR-T cells containing anti-CD318 single-chain variable fragment (anti-CD318 scFv), CD3ζ, CD28, and Toll-like receptor 2 (TLR2) domains. Next, we evaluated the function of these CAR-T cells in vitro in terms of surface phenotype changes, cytotoxicity and cytokine secretion when they encountered CD318+ CRC cells. Finally, we established two different xenograft mouse models to assess in vivo antitumor activity. The results showed that CAR318 T cells were significantly activated and exhibited strong cytotoxicity and cytokine-secreting abilities against CRC cells in vitro. Furthermore, CAR318 T cells induced CRC regression in different xenograft mouse models and suppressed tumors compared with CAR19 T cells. In summary, our work demonstrates that CAR318 T cells possess strong antitumor capabilities and represent a promising therapeutic approach for CRC.