Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
IRCCS Humanitas Clinical and Research Center, Rozzano, Italy.
Cancer Immunol Res. 2019 Nov;7(11):1775-1788. doi: 10.1158/2326-6066.CIR-19-0168. Epub 2019 Sep 4.
CCRL2 is a nonsignaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that promotes chemotaxis of leukocytes, including macrophages and natural killer (NK) cells. In addition, CCRL2 controls the inflammatory response in different pathologic settings, such as hypersensitivity, inflammatory arthritis, and experimental autoimmune encephalitis. Here, we investigated the role of CCRL2 in the regulation of lung cancer-related inflammation. The genetic deletion of promoted tumor progression in urethane-induced and in / lung tumor mouse models. Similarly, a -mutant lung tumor displayed enhanced growth in -deficient mice. This phenotype was associated with a reduced inflammatory infiltrate characterized by the impaired recruitment of several leukocyte populations including NK cells. Bone marrow chimeras showed that CCRL2 expression by the nonhematopoietic cell compartment was responsible for the increased tumor formation observed in -mutant -deficient mice. In human and mouse lungs, CCRL2 was expressed by a fraction of CD31 endothelial cells, where it could control NK infiltration. Elevated CCRL2 expression in biopsies from human lung adenocarcinoma positively correlated with clinical outcome. These results provide evidence for a crucial role of CCRL2 in shaping an anti-lung tumor immune response.
CCRL2 是一种无信号转导的七跨膜域受体。CCRL2 结合趋化素，趋化素能促进白细胞（包括巨噬细胞和自然杀伤 (NK) 细胞）的趋化作用。此外，CCRL2 还控制着不同病理环境下的炎症反应，如过敏、炎症性关节炎和实验性自身免疫性脑脊髓炎。在这里，我们研究了 CCRL2 在调节肺癌相关炎症中的作用。在尿嘧啶诱导的和 / 肺癌小鼠模型中，缺失促进了肿瘤的进展。同样，-突变的肺肿瘤在 -缺陷小鼠中显示出更强的生长。这种表型与炎症浸润减少有关，其特征是包括 NK 细胞在内的几种白细胞群的募集受损。骨髓嵌合体表明，非造血细胞区室中 CCRL2 的表达是导致 -突变 -缺陷小鼠中观察到的肿瘤形成增加的原因。在人和小鼠的肺部，CCRL2 由一部分 CD31 内皮细胞表达，它可以控制 NK 细胞的浸润。从人肺腺癌活检中检测到的 CCRL2 表达升高与临床结局呈正相关。这些结果为 CCRL2 在塑造抗肺癌免疫反应中发挥关键作用提供了证据。
