Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P R China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, P R China.
Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P R China.
Cancer Genet. 2022 Nov;268-269:103-110. doi: 10.1016/j.cancergen.2022.10.003. Epub 2022 Oct 18.
PD-1/PD-L1 pathway caused immunosuppression accounts, at least partly, for the poor therapeutic effect of Chimeric Antigen Receptor T (CAR-T) on solid tumors. In this study, we designed and prepared CAR-T cells that could secrete PD-L1 blocking antibody and target Mesothelin antigen (Sec-MesoCAR-T), to remove the immunosuppressive effect of tumor on CAR-T cells, thereby increasing the therapeutic effect of CAR-T cells on pancreatic cancer. The CAR-T cells that could not secret PD-L1 blocking antibodies (MesoCAR-T) were used as a control. Sec-MesoCAR-T cells showed an enhanced inhibitory effect on BxPC-3 tumor than MesoCAR-T cells in vitro and in vivo. Besides, Sec-MesoCAR-T cells secreted higher level of cytokines including IL-2, IL-6 and IFN-γ in vitro than MesoCAR-T cells. Following injection, there were significantly more CAR-T cells in the peripheral blood of Sec-MesoCAR-T group than that of MesoCAR-T group. This work demonstrated that the PD-L1 antibody secreted by Sec-MesoCAR-T cells relieved the immunosuppressive effect of pancreatic cancer on CAR-T cells and improved the anti-tumor activity of CAR-T cells, which has a good guiding significance for the clinical application of CAR-T cells in treating solid tumors.
PD-1/PD-L1 通路引起的免疫抑制至少部分解释了嵌合抗原受体 T（CAR-T）对实体瘤治疗效果不佳的原因。在这项研究中，我们设计并制备了能够分泌 PD-L1 阻断抗体并靶向间皮素抗原（Sec-MesoCAR-T）的 CAR-T 细胞，以消除肿瘤对 CAR-T 细胞的免疫抑制作用，从而提高 CAR-T 细胞对胰腺癌的治疗效果。未分泌 PD-L1 阻断抗体的 CAR-T 细胞（MesoCAR-T）被用作对照。Sec-MesoCAR-T 细胞在体外和体内对 BxPC-3 肿瘤的抑制作用均强于 MesoCAR-T 细胞。此外，Sec-MesoCAR-T 细胞在体外分泌的细胞因子（包括 IL-2、IL-6 和 IFN-γ）水平高于 MesoCAR-T 细胞。注射后，Sec-MesoCAR-T 组外周血中的 CAR-T 细胞明显多于 MesoCAR-T 组。这项工作表明，Sec-MesoCAR-T 细胞分泌的 PD-L1 抗体缓解了胰腺癌对 CAR-T 细胞的免疫抑制作用，提高了 CAR-T 细胞的抗肿瘤活性，这对 CAR-T 细胞在治疗实体瘤中的临床应用具有很好的指导意义。
