Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Fred and Pamela Buffet Cancer Center at University of Nebraska Medical Center, Omaha, Nebraska.
Cancer Res. 2018 Oct 1;78(19):5600-5617. doi: 10.1158/0008-5472.CAN-18-0562. Epub 2018 Aug 15.
Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of antitumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is a member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized. In this study, we show that NRP2 is expressed during macrophage differentiation, is induced by tumor cells, and regulates phagocytosis in macrophages. Furthermore, NRP2 in TAM promoted efferocytosis and facilitated tumor growth. Deletion of NRP2 from TAM impaired the clearance of apoptotic tumor cells and increased secondary necrosis within tumors. This resulted in a break in the immune tolerance and reinitiated antitumor immune responses, characterized by robust infiltration of CD8 T and natural killer cells. This result suggests NRP2 may act as a molecular mediator that connects efferocytosis and immune suppression. Deletion of NRP2 in TAM downregulated several immunosuppressive and tumor-promoting genes and upregulated immunostimulatory genes in the myeloid compartment. Taken together, our study demonstrates that TAM-derived NRP2 plays a crucial role in tumor promotion through efferocytosis, opening the enticing option for the development of effective immunotherapy targeting TAM. Neuropilin-2 in macrophages promotes tumor growth by regulating efferocytosis of apoptotic tumor cells and orchestrating immune suppression. http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg .
肿瘤相关巨噬细胞（TAM）与肿瘤发生以及抗肿瘤免疫反应的调节密切相关，已成为潜在的免疫治疗靶点。最近的证据表明，TAM 通过吞噬作用以免疫沉默的方式吞噬肿瘤微环境中的凋亡肿瘤细胞，从而维持免疫抑制微环境。将吞噬作用和免疫抑制偶联的信号转导途径尚不清楚。神经纤毛蛋白-2（NRP2）是膜相关神经纤毛家族的成员，已在不同的免疫细胞中报道，但特征描述较差。在这项研究中，我们表明 NRP2 在巨噬细胞分化过程中表达，被肿瘤细胞诱导，并调节巨噬细胞的吞噬作用。此外，TAM 中的 NRP2 促进吞噬作用并促进肿瘤生长。从 TAM 中删除 NRP2 会损害凋亡肿瘤细胞的清除，并增加肿瘤内的继发性坏死。这导致免疫耐受破裂，并重新引发抗肿瘤免疫反应，其特征是 CD8 T 和自然杀伤细胞的大量浸润。这一结果表明 NRP2 可能作为连接吞噬作用和免疫抑制的分子介质。TAM 中 NRP2 的缺失下调了髓系细胞中几个免疫抑制和促进肿瘤的基因，并上调了免疫刺激基因。总之，我们的研究表明，TAM 衍生的 NRP2 通过吞噬作用在肿瘤促进中发挥关键作用，为开发针对 TAM 的有效免疫疗法开辟了诱人的选择。巨噬细胞中的神经纤毛蛋白-2通过调节凋亡肿瘤细胞的吞噬作用并协调免疫抑制来促进肿瘤生长。http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg 。
