肿瘤细胞治疗研究
英文原题：Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.
Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.
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限制嵌合抗原受体（CAR）T细胞成功治疗实体瘤的主要障碍之一，是不利的肿瘤微环境（TME）。我们对靶向碳酸酐酶IX（CAIX）的CAR-T 细胞进行工程化改造，使其分泌抗PD-L1单克隆抗体（mAb），命名为免疫恢复型（IR）CAR G36-PDL1。我们在一种人源化透明细胞肾细胞癌（ccRCC）原位小鼠模型中测试CAR-T 细胞。该模型重建了部分HLA匹配、来源于胎儿CD34+造血干细胞（HSC）的人白细胞，并在肾包膜下接种人ccRCC skrc-59细胞。与不具备免疫恢复作用的CAR-T 相比，与肿瘤细胞半相合的G36-PDL1 CAR-T 表现出强效抗肿瘤作用。TME分析显示，G36-PDL1 CAR-T 通过促进肿瘤杀伤细胞毒性、减少M2巨噬细胞和耗竭CD8+ T细胞等免疫抑制细胞成分，并增强滤泡辅助性T（Tfh）细胞与B细胞的相互作用，恢复了活跃的抗肿瘤免疫。
One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME).
We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1.
We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34 + hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule.
G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8 + T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.
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