MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland.
Clin Cancer Res. 2014 Dec 15;20(24):6452-64. doi: 10.1158/1078-0432.CCR-14-1236. Epub 2014 Oct 15.
Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown.
Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma.
Clever-1-deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity.
This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer.
免疫抑制性白细胞和脉管系统是调节肿瘤进展的重要宿主细胞成分。Clever-1/Stabilin-1 是一种多功能的清道夫和黏附受体，在 II 型巨噬细胞和淋巴管内皮细胞的亚群中持续存在，但它在癌症中的功能作用尚不清楚。
在这里，我们生成了完整的 Clever-1 敲除小鼠和细胞特异性的缺乏 Clever-1 的巨噬细胞或内皮细胞缺失小鼠。我们还使用抗 Clever-1 抗体治疗治疗 B16 黑色素瘤和 EL-4 淋巴瘤。
与野生型（WT）对照相比，Clever-1 缺陷小鼠的原发性和转移性肿瘤较小。仅在巨噬细胞或血管内皮细胞中缺乏 Clever-1 的小鼠的原发性肿瘤生长受到抑制，但转移瘤生长不受抑制。抗 Clever-1 抗体治疗抑制了 WT 小鼠的肿瘤进展。无论是基因敲除还是治疗性敲除功能性 Clever-1，都会导致肿瘤中免疫抑制性白细胞类型的数量减少。功能上的 Clever-1 介导了免疫抑制性白细胞与异常表达 Clever-1 的肿瘤内血管的结合，以及肿瘤细胞通过淋巴管的运输。抗体治疗并未加重自身免疫。
这项工作确定了 II 型巨噬细胞和肿瘤血管中的 Clever-1 是癌症中的一种新的免疫抑制分子。我们发现 Clever-1 支持肿瘤浸润淋巴细胞与肿瘤血管的结合，增加了我们对白细胞向肿瘤浸润的理解。抗 Clever-1 抗体治疗在体内减弱 WT 小鼠肿瘤进展的能力具有治疗相关性。因此，Clever-1 可能成为调节癌症中免疫逃逸和淋巴扩散的新靶点。
