Yu Yen-Rei A, Fong Alan M, Combadiere Christophe, Gao Ji-Liang, Murphy Philip M, Patel Dhavalkumar D
Thurston Arthritis Research Center and the Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Int J Cancer. 2007 Jul 15;121(2):316-22. doi: 10.1002/ijc.22660.
Innate immunity is critically important for tumor surveillance and regulating tumor metastasis. Fractalkine (FKN, CX3CL1), operating through the receptor CX3CR1, is an effective chemoattractant and adhesion receptor for NK cells and monocytes, important constituents of the innate immune response. Previous studies have shown that over-expression of CX3CL1 by tumor cells enhances antitumor responses. However, since most tumors do not express CX3CL1, it remains unclear if CX3CL1/CX3CR1 has a role in tumor immunity in the absence of ligand over-expression. To determine the role of CX3CL1 and CX3CR1 in regulating antitumor immune responses, we tested the response of wildtype and CX3CR1-deficient animals to unmanipulated B16 melanoma that does not express CX3CL1. We studied the distribution and trafficking of mononuclear cells (MNC) under homeostatic conditions and in the presence of B16 metastatic melanoma, cytotoxic activity, and cytokine production in wild-type and CX3CR1-deficient animals. We found that B16-treated CX3CR1-/- mice had increased lung tumor burden and cachexia. There was a selective reduction of monocytes and NK cells in the lungs of CX3CR1-deficient animals under homeostatic conditions and in response to B16. CX3CR1-deficient NK cells effectively killed B16 cells in cytotoxicity assays. However, CX3CR1-deficient NK cells exhibited a tumorigenic cytokine production profile with defective IFN-gamma expression and enhanced IL-6 production in response to TLR3 activation with polyIC. Our studies indicate that CX3CR1 is an important contributor to innate immunity at multiple levels. Its role in tumor immunity is not limited by expression of CX3CL1 by tumor cells.
固有免疫对于肿瘤监测和调节肿瘤转移至关重要。趋化因子（FKN，CX3CL1）通过受体CX3CR1发挥作用，是天然免疫反应的重要组成部分——自然杀伤（NK）细胞和单核细胞的有效趋化因子和黏附受体。先前的研究表明，肿瘤细胞过表达CX3CL1可增强抗肿瘤反应。然而，由于大多数肿瘤不表达CX3CL1，因此在没有配体过表达的情况下，CX3CL1/CX3CR1是否在肿瘤免疫中发挥作用仍不清楚。为了确定CX3CL1和CX3CR1在调节抗肿瘤免疫反应中的作用，我们测试了野生型和CX3CR1缺陷型动物对未处理的不表达CX3CL1的B16黑色素瘤的反应。我们研究了稳态条件下以及存在B16转移性黑色素瘤时野生型和CX3CR1缺陷型动物体内单核细胞（MNC）的分布和迁移、细胞毒性活性以及细胞因子产生情况。我们发现，经B16处理的CX3CR1 - / - 小鼠的肺部肿瘤负荷增加且出现恶病质。在稳态条件下以及对B16的反应中，CX3CR1缺陷型动物肺部的单核细胞和NK细胞选择性减少。在细胞毒性试验中，CX3CR1缺陷型NK细胞能有效杀伤B16细胞。然而，CX3CR1缺陷型NK细胞在受到多聚肌苷酸（polyIC）激活TLR3时，表现出具有致瘤性的细胞因子产生谱，即干扰素 - γ（IFN - γ）表达缺陷且白细胞介素 - 6（IL - 6）产生增加。我们的研究表明，CX3CR1在多个层面上是固有免疫的重要贡献者。其在肿瘤免疫中的作用不受肿瘤细胞CX3CL1表达的限制。
