Co-Expression of IL-7 Improves NKG2D-Based CAR T Cell Therapy on Prostate Cancer by Enhancing the Expansion and Inhibiting the Apoptosis and Exhaustion
Co-Expression of IL-7 Improves NKG2D-Based CAR T Cell Therapy on Prostate Cancer by Enhancing the Expansion and Inhibiting the Apoptosis and Exhaustion
复制标题
IL-7 的共表达通过增强扩张并抑制细胞凋亡和耗竭改善基于 NKG2D 的 CAR T 细胞对前列腺癌的治疗
DOI：
10.3390/cancers12071969
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发表时间：
2020-07-01
期刊：
影响因子：
5.2
通讯作者：
Jiang, Wenzheng
中科院分区：
文献类型：
--
作者：
He, Cong;Zhou, Ying;Jiang, Wenzheng
嵌合抗原受体（CAR）T细胞治疗是治疗实体瘤的一种有前途的方法，但治疗效果有限。前列腺癌是一种典型的实体性恶性肿瘤，具有侵袭性和高度免疫抑制的微环境。NKG 2D受体的配体主要在许多癌细胞（包括前列腺癌）上表达。在这项研究中，我们利用基于NKG 2D的CAR治疗前列腺癌，并通过共表达IL-7来提高治疗效果。结果显示，与未转导的T细胞相比，NKG 2D-CAR T细胞在体外和体内对前列腺癌的细胞毒性显著增加。此外，将IL-7基因引入NKG 2D-CAR骨架以抗原依赖性方式增强了IL-7的产生。NKG 2DIL 7-CAR T细胞在体外16 h和72 h时表现出更好的抗肿瘤疗效，并且在异种移植模型中更有效地抑制肿瘤生长。在机制上，CD 8 + T细胞增殖和Bcl-2表达增强、凋亡和耗竭减少以及低分化细胞表型增加可能是NKG 2DIL 7-CAR T细胞持久性和存活率提高的原因。总之，这些研究结果表明，NKG 2D是前列腺癌CAR T细胞治疗的一种有前途的选择，IL-7对基于NKG 2D的CAR T细胞免疫治疗具有增强作用，为前列腺癌单独或与IL-7联合提供了一种新的过继细胞治疗。
Chimeric antigen receptor (CAR) T-cell therapy is a promising approach in treating solid tumors but the therapeutic effect is limited. Prostate cancer is a typical solid malignancy with invasive property and a highly immunosuppressive microenvironment. Ligands for the NKG2D receptor are primarily expressed on many cancer cells, including prostate cancer. In this study, we utilized NKG2D-based CAR to treat prostate cancer, and improved the therapeutic effect by co-expression of IL-7. The results showed that NKG2D-CAR T cells performed significantly increased cytotoxicity against prostate cancer compared to non-transduced T cells in vitro and in vivo. Moreover, the introduction of the IL-7 gene into the NKG2D-CAR backbone enhanced the production of IL-7 in an antigen-dependent manner. NKG2DIL7-CAR T cells exhibited better antitumor efficacy at 16 h and 72 h in vitro, and inhibited tumor growth in xenograft models more effectively. In mechanism, enhanced proliferation and Bcl-2 expression in CD8+ T cells, decreased apoptosis and exhaustion, and increased less-differentiated cell phenotype may be the reasons for the improved persistence and survival of NKG2DIL7-CAR T cells. In conclusion, these findings demonstrated that NKG2D is a promising option for CAR T-cell therapy on prostate cancer, and IL-7 has enhanced effect on NKG2D-based CAR T-cell immunotherapy, providing a novel adoptive cell therapy for prostate cancer either alone or in combination with IL-7.