Department of hepatobiliary surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Department of general surgery, General Hospital of central theater command, Wuhan, 430000, China.
Med Oncol. 2023 Mar 22;40(4):123. doi: 10.1007/s12032-023-01959-1.
Chimeric antigen receptor T cell (CAR-T) is regarded as a promising therapy for malignancies. In our previous clinical trial targeted colorectal tumors, we found that CAR-T cells experienced poor proliferation and persistence in tumor sites. To improve the efficacy of CAR-T cells, we introduced CD27 co-stimulation signal into the established system and found that the CEA28BB27Z CAR-T cells exhibited enhanced proliferation and anti-tumor activity. Next, we demonstrated that the CEA28BB27Z CAR-T cells expressed less immune checkpoint receptors and generated more CD4 and CD8 memory stem T (T) cells compared with other CARs during constant antigen stimulation. Furthermore, our data revealed that the different combination of co-stimulation signal affected the mitochondrial dynamics of CAR-T cells, and CEA28BB27Z CAR-T cells maintained more fused mitochondrial network compared with others. Finally, we validated the superior antitumor capacity of the CEA28BB27Z CAR-T cells in xenograft models. Our findings suggest that CD27 co-stimulation signals play a key role in improving the anti-tumor efficacy of CAR-T cells.
嵌合抗原受体 T 细胞（CAR-T）被认为是治疗恶性肿瘤的一种有前途的疗法。在我们之前针对结直肠肿瘤的临床试验中，我们发现 CAR-T 细胞在肿瘤部位的增殖和持久性较差。为了提高 CAR-T 细胞的疗效，我们在已建立的系统中引入了 CD27 共刺激信号，发现 CEA28BB27Z CAR-T 细胞表现出增强的增殖和抗肿瘤活性。接下来，我们证明与其他 CAR 相比，CEA28BB27Z CAR-T 细胞在持续抗原刺激下表达较少的免疫检查点受体，并产生更多的 CD4 和 CD8 记忆性干 T（T）细胞。此外，我们的数据表明，不同的共刺激信号组合会影响 CAR-T 细胞的线粒体动力学，与其他 CAR 相比，CEA28BB27Z CAR-T 细胞保持更多融合的线粒体网络。最后，我们在异种移植模型中验证了 CEA28BB27Z CAR-T 细胞的优越抗肿瘤能力。我们的研究结果表明，CD27 共刺激信号在提高 CAR-T 细胞的抗肿瘤疗效方面发挥着关键作用。
