Shanghai Yihao Biological Technology Co, Ltd, Shanghai 200231, China.
Institute of Tumor of Nantong Tumor Hospital, No. 30, North Tongyang Road, Pingchao Town, Tongzhou District, Nantong City, Jiangsu Province 226361, China.
Hum Immunol. 2021 Feb;82(2):130-138. doi: 10.1016/j.humimm.2020.12.002. Epub 2020 Dec 16.
Chimeric antigen receptor T (CAR T) cell therapy is a new pillar in cancer therapeutics, and has been successfully used for the treatment of cancers, including acute lymphoblastic leukemia and solid cancers. Following immune attack, many tumors upregulate inhibitory ligands which bind to inhibitory receptors on T cells. For example, the interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands (widely known as PD-L1) on a target tumor limits the efficacy of CAR T cells therapy against poorly responding tumors. Here, we use mesothelin (MSLN)-expressing human ovarian cancer cells (SKOV3) and human colon cancer cells (HCT116) to investigate whether PD-1-mediated T cell exhaustion affects the anti-tumor activity of MSLN-targeted CAR T cells. We utilized cell-intrinsic PD-1-targeting shRNA overexpression strategy, resulting in a significant PD-1 silencing in CAR T cells. The reduction of PD-1 expression on T cell surface strongly augmented CAR T cell cytokine production and cytotoxicity towards PD-L1-expressing cancer cells in vitro. This study indicates the enhanced anti-tumor efficacy of PD-1-silencing MSLN-targeted CAR T cells against several cancers and suggests the potential of other specific gene silencing on the immune checkpoints to enhance the CAR T cell therapies against human tumors.
嵌合抗原受体 T（CAR T）细胞疗法是癌症治疗的新支柱，已成功用于治疗癌症，包括急性淋巴细胞白血病和实体瘤。在免疫攻击后，许多肿瘤上调抑制性配体，这些配体与 T 细胞上的抑制性受体结合。例如，激活的 T 细胞上的程序性细胞死亡蛋白 1（PD-1）与其靶肿瘤上的配体（通常称为 PD-L1）之间的相互作用限制了 CAR T 细胞疗法对反应不佳的肿瘤的疗效。在这里，我们使用表达间皮素（MSLN）的人卵巢癌细胞（SKOV3）和人结肠癌细胞（HCT116）来研究 PD-1 介导的 T 细胞耗竭是否会影响 MSLN 靶向 CAR T 细胞的抗肿瘤活性。我们利用细胞内在的 PD-1 靶向 shRNA 过表达策略，导致 CAR T 细胞中的 PD-1 沉默显著。T 细胞表面 PD-1 表达的减少强烈增强了 CAR T 细胞对体外表达 PD-L1 的癌细胞的细胞因子产生和细胞毒性。这项研究表明，针对几种癌症的 PD-1 沉默 MSLN 靶向 CAR T 细胞具有增强的抗肿瘤功效，并表明针对免疫检查点的其他特定基因沉默具有增强针对人类肿瘤的 CAR T 细胞疗法的潜力。
