肿瘤细胞治疗研究
英文原题：Expressing IL-15/IL-18 and CXCR2 improve infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer.
此前，我们构建了 EGFRvIII 靶向 CAR-T 细胞，为治疗晚期乳腺癌带来了希望。
我们此前已生成靶向 EGFRvIII 的 CAR-T 细胞，为晚期乳腺癌治疗带来希望。然而，该疗法抗肿瘤效力有限，可能是因为治疗性 T 细胞在乳腺肿瘤部位积累不足、持续存在能力较弱。趋化因子 CXCL 在乳腺癌肿瘤环境中高表达，CXCR2 是其主要受体。本研究发现，CXCR2 可显著改善 CAR-T 细胞在体内外的迁移和肿瘤特异性积累。但 CXCR2 CAR-T 细胞的抗肿瘤效应减弱，可能与 T 细胞凋亡有关。IL-15 和 IL-18 等细胞因子可刺激 T 细胞增殖。因此，我们生成了可合成 IL-15 或 IL-18 的 CXCR2 CAR。共同表达 IL-15 或 IL-18 可显著抑制 T 细胞耗竭和凋亡，并增强 CXCR2 CAR-T 细胞体内抗肿瘤活性。此外，在 CXCR2 CAR-T 细胞中共同表达 IL-15 或 IL-18 未引起毒性。这些发现为未来治疗进展期乳腺癌提供了一种潜在策略，即在 CXCR2 CAR-T 细胞中共同表达 IL-15 或 IL-18。
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.
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