我们之前制备出EGFRvIII靶向CAR-T细胞，为治疗晚期乳腺癌带来了希望。然而，EGFRvIII靶向CAR-T细胞的抗肿瘤效果有限，可能是因为治疗性T细胞在乳腺癌肿瘤部位的积累和存留量减少。CXCLs在乳腺癌肿瘤环境中高表达，CXCR2是CXCLs的主要受体。在此，CXCR2可显著提高CAR-T细胞的移行和肿瘤特异性积累，无论在体内还是体外。然而，CXCR2 CAR-T细胞的抗肿瘤效应较弱，可能是T细胞凋亡的结果。细胞因子可以刺激T细胞增殖，例如白细胞介素（IL）-15和IL-18。因此，我们产生了含有合成IL-15或IL-18产物的CXCR2 CAR。共表达IL-15或IL-18可以显著抑制T细胞的衰竭和凋亡，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不会造成毒性。这些发现为将来在CXCR2 CAR-T细胞中共表达IL-15或IL-18的潜在治疗策略提供了希望，用于治疗晚期乳腺癌。版权所有©2023 Elsevier Inc.。保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.