State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
Biochem Pharmacol. 2023 Jun;212:115536. doi: 10.1016/j.bcp.2023.115536. Epub 2023 Apr 5.
Previously, we have generated EGFRvIII-targeting CAR-T cells and brought hope for treating advanced breast cancer. However, EGFRvIII-targeting CAR-T cells were defined limited anti-tumor efficacy, which might be due to reduced accumulation, persistence of therapeutic T cells in tumor site of breast cancer. CXCLs were highly expressed in tumor environment of breast cancer and CXCR2 is the main receptor for CXCLs. Here, CXCR2 could significantly improve the trafficking and tumor specific accumulation of CAR-T cells both in vivo and in vitro. However, the anti-tumor effect of CXCR2 CAR-T cells were weaken which might be results of the apoptosis of T cells. Cytokines could stimulate Tcell proliferation, such as interleukin (IL)-15 and IL-18. Then, we generated CXCR2 CAR with synthetic IL-15 or IL-18 production. Co-expressing IL-15 or IL-18 could significantly suppress the exhaustion and apoptosis of T cells and enhanced the anti-tumor activity of CXCR2 CAR-T cells in vivo. Further, coexpression IL-15 or IL-18 in CXCR2 CAR-T cells did not cause toxicity. These findings provide a potential therapy strategy of co-expression IL-15 or IL-18 in CXCR2 CAR-T cells for the treatment of advancing breast cancer in the future.
先前，我们已经生成了针对 EGFRvIII 的 CAR-T 细胞，为治疗晚期乳腺癌带来了希望。然而，针对 EGFRvIII 的 CAR-T 细胞的抗肿瘤疗效有限，这可能是由于治疗性 T 细胞在乳腺癌肿瘤部位的积累和持续存在减少所致。趋化因子（CXCLs）在乳腺癌的肿瘤微环境中高度表达，而 CXCR2 是 CXCLs 的主要受体。在这里，CXCR2 可显著改善 CAR-T 细胞在体内和体外的迁移和肿瘤特异性积累。然而，CXCR2 CAR-T 细胞的抗肿瘤作用减弱，这可能是由于 T 细胞凋亡所致。细胞因子可刺激 T 细胞增殖，如白细胞介素（IL）-15 和 IL-18。然后，我们生成了具有合成 IL-15 或 IL-18 产生能力的 CXCR2 CAR。共表达 IL-15 或 IL-18 可显著抑制 T 细胞的耗竭和凋亡，并增强 CXCR2 CAR-T 细胞在体内的抗肿瘤活性。此外，在 CXCR2 CAR-T 细胞中共表达 IL-15 或 IL-18 不会引起毒性。这些发现为未来治疗进展期乳腺癌提供了一种在 CXCR2 CAR-T 细胞中共表达 IL-15 或 IL-18 的潜在治疗策略。
