Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
Cancer Immunol Res. 2018 Oct;6(10):1186-1198. doi: 10.1158/2326-6066.CIR-18-0045. Epub 2018 Aug 14.
The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4 mice exhibited slowed tumor progression compared with CXCR4 mice in an inducible melanocyte mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4 mice as compared with myeloid cells from CXCR4 mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4 mice. NK cells from CXCR4 mice also exhibited increased tumor cell killing capacity , based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4 neutrophils. Furthermore, enhanced NK cell activity in CXCR4 mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4 mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. .
趋化因子受体 CXCR4 参与癌症的生长、侵袭和转移。多项有前景的 CXCR4 拮抗剂已在临床前研究中显示可阻止肿瘤转移，目前正在进行评估这些药物在癌症患者中的有效性的临床试验。然而，靶向 CXCR4 对免疫细胞的具体影响尚不清楚。在这里，我们证明了骨髓细胞（CXCR4）中 CXCR4 的基因缺失增强了抗肿瘤免疫反应，导致黑色素瘤肿瘤生长明显减少。此外，在诱导性黑素细胞小鼠模型中，与 CXCR4 小鼠相比，CXCR4 小鼠的肿瘤进展速度较慢。与 CXCR4 小鼠的骨髓细胞相比，CXCR4 小鼠中 Fas 配体（FasL）表达的骨髓细胞百分比减少。相比之下，在 CXCR4 小鼠中生长的肿瘤中，表达 FasL 的自然杀伤（NK）细胞的百分比增加。基于对 NK 敏感的 Yac-1 细胞的清除，来自 CXCR4 小鼠的 NK 细胞还显示出增强的肿瘤细胞杀伤能力。NK 细胞对 Yac-1 细胞的杀伤作用以 FasL 依赖的方式发生，这部分依赖于 CXCR4 中性粒细胞的存在。此外，CXCR4 小鼠中 NK 细胞活性的增强也与特定白细胞亚群产生的白细胞介素 18（IL18）增加有关。这些数据表明，骨髓细胞中 CXCR4 介导的信号抑制了 NK 细胞介导的肿瘤监视，从而促进了肿瘤生长。将 CXCR4 的肽拮抗剂系统递送至荷瘤 CXCR4 小鼠可增强 NK 细胞的激活并减少肿瘤生长，这支持了在某些癌症中使用 CXCR4 拮抗剂的潜在临床意义。
