Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and.
FASEB J. 2019 May;33(5):6596-6608. doi: 10.1096/fj.201802067RR. Epub 2019 Feb 25.
Blockade of immune-checkpoint programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 can enhance effector T-cell responses. However, the lack of response in many patients to checkpoint-inhibitor therapies emphasizes the need for combination immunotherapies to pursue maximal antitumor efficacy. We have previously demonstrated that antagonism of C-X-C chemokine receptor type 4 (CXCR4) by plerixafor (AMD3100) can decrease regulatory T (T)-cell intratumoral infiltration. Therefore, a combination of these 2 therapies might increase antitumor effects. Here, we evaluated the antitumor efficacy of AMD3100 and anti-PD-1 (αPD-1) antibody alone or in combination in an immunocompetent syngeneic mouse model of ovarian cancer. We found that AMD3100, a highly specific CXCR4 antagonist, directly down-regulated the expression of both C-X-C motif chemokine 12 (CXCL12) and CXCR4 and in tumor cells. AMD3100 and αPD-1 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice when given as monotherapy. Combination of these 2 agents significantly enhanced antitumor effects compared with single-agent administration. Benefits of tumor control and animal survival were associated with immunomodulation mediated by these 2 agents, which were characterized by increased effector T-cell infiltration, increased effector T-cell function, and increased memory T cells in tumor microenvironment. Intratumoral T cells were decreased, and conversion of T cells into T helper cells was increased by AMD3100 treatment. Intratumoral myeloid-derived suppressor cells were decreased by the combined treatment, which was associated with decreased IL-10 and IL-6 in the ascites. Also, the combination therapy decreased suppressive leukocytes and facilitated M2-to-M1 macrophage polarization in the tumor. These results suggest that AMD3100 could be used to target the CXCR4-CXCL12 axis to inhibit tumor growth and prevent multifaceted immunosuppression alone or in combination with αPD-1 in ovarian cancer, which could be clinically relevant to patients with this disease.-Zeng, Y., Li, B., Liang, Y., Reeves, P. M., Qu, X., Ran, C., Liu, Q., Callahan, M. V., Sluder, A. E., Gelfand, J. A., Chen, H., Poznansky, M. C. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.
阻断免疫检查点程序性细胞死亡蛋白 1 (PD-1) 或程序性细胞死亡配体 1 可以增强效应 T 细胞的反应。然而，许多患者对检查点抑制剂治疗没有反应，这强调了需要联合免疫疗法以追求最大的抗肿瘤疗效。我们之前已经证明，用plerixafor（AMD3100）拮抗 C-X-C 趋化因子受体 4 (CXCR4) 可以减少调节性 T (T) 细胞在肿瘤内的浸润。因此，这两种疗法的联合可能会增加抗肿瘤作用。在这里，我们评估了 AMD3100 和抗 PD-1（αPD-1）抗体单独或联合在卵巢癌免疫功能正常的同种异体小鼠模型中的抗肿瘤疗效。我们发现，AMD3100，一种高度特异性的 CXCR4 拮抗剂，直接下调肿瘤细胞中 C-X-C 基序趋化因子 12 (CXCL12) 和 CXCR4 的表达。AMD3100 和 αPD-1 单独给药时均显著抑制肿瘤生长并延长荷瘤小鼠的生存时间。与单药治疗相比，这两种药物联合使用显著增强了抗肿瘤作用。肿瘤控制和动物生存的益处与这两种药物介导的免疫调节有关，其特征是效应 T 细胞浸润增加、效应 T 细胞功能增强和肿瘤微环境中记忆 T 细胞增加。AMD3100 治疗可减少肿瘤内 T 细胞，并增加 T 细胞向辅助性 T 细胞的转化。联合治疗可减少肿瘤内髓源性抑制细胞，同时减少腹水 IL-10 和 IL-6。此外，联合治疗还可减少抑制性白细胞，并促进肿瘤中 M2 向 M1 巨噬细胞的极化。这些结果表明，AMD3100 可用于靶向 CXCR4-CXCL12 轴，单独或与卵巢癌中的 αPD-1 联合抑制肿瘤生长并预防多方面免疫抑制，这可能与患有这种疾病的患者具有临床相关性。-曾，Y.，李，B.，梁，Y.，里夫斯，P. M.，曲，X.，然，C.，刘，Q.，卡勒汉，M. V.，斯卢德，A. E.，杰斐逊，J. A.，陈，H.，波赞斯基，M. C. 双重阻断 CXCL12-CXCR4 和 PD-1-PD-L1 通路通过预防肿瘤微环境中的免疫抑制延长卵巢荷瘤小鼠的生存时间。
