Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer
Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer
复制标题
间皮素是嵌合抗原受体 T 细胞治疗胃癌的靶标
DOI：
10.1186/s13045-019-0704-y
复制
发表时间：
2019-02-18
影响因子：
28.5
通讯作者：
Li, Peng
中科院分区：
文献类型：
--
作者：
Lv, Jiang;Zhao, Ruocong;Li, Peng
背景胃癌（GC）是亚洲常见的恶性肿瘤，目前缺乏靶向治疗方法.间皮素（MSLN）已被报道在GC组织中表达，并可被嵌合抗原受体（CAR）T细胞靶向。据报道，靶向CAR-T的间皮素在间皮瘤、肺癌、乳腺癌和胰腺癌中有应用。然而，使用抗MSLN CAR T细胞来治疗GC.MethodsWe验证MSLN在原代人GC组织和GC细胞系中的表达，然后用含有MSLN scFv（单链可变片段）、CD 3 β、CD 28和DAP 10胞内信号结构域（M28 z10）的CAR重定向T细胞以靶向MSLN。我们在体外评估了这些CAR T细胞在遇到MSLN+ GC细胞时的细胞毒性、细胞因子分泌和表面表型变化方面的功能。结果M28 z10 T细胞在体外对胃癌细胞具有较强的杀伤活性，并能分泌大量的精氨酸。此外，细胞表面表型表明在靶细胞刺激后M28 z10 T细胞显著活化。M28 z10 T细胞在不同的异种移植小鼠模型中诱导GC消退，并且与腹腔内和肺转移性GC模型中的GFP转导的T细胞相比，延长了这些小鼠的存活。重要的是，肿瘤周围递送策略可以改善CAR-T细胞向肿瘤组织的浸润，并显著抑制皮下GC模型中GC的生长。结论这些结果表明M28 z10 T细胞具有较强的抗肿瘤活性，代表了一种有希望的GC治疗方法。
BackgroundGastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied.MethodsWe verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes when they encountered MSLN+ GC cells. We also established four different xenograft GC mouse models to assess in vivo antitumor activity.ResultsM28z10 T cells exhibited strong cytotoxicity and cytokine-secreting ability against GC cells in vitro. In addition, cell surface phenotyping suggested significant activation of M28z10 T cells upon target cell stimulation. M28z10 T cells induced GC regression in different xenograft mouse models and prolonged the survival of these mice compared with GFP-transduced T cells in the intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue and significantly suppress the growth of GC in a subcutaneous GC model.ConclusionThese results demonstrate that M28z10 T cells possess strong antitumor activity and represent a promising therapeutic approach to GC.