Department of Pathology and Pathophysiology, and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, 310058, Hangzhou, China.
Oncogene. 2018 Sep;37(37):5088-5100. doi: 10.1038/s41388-018-0337-6. Epub 2018 May 24.
The Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp2) is generally considered to be an oncogene owing to its ability in enhancing the malignancy of multiple types of tumor cells; however, its role in modulating tumor immunity remains largely elusive. Here, we reported that myeloid-restricted ablation of Shp2 suppressed melanoma growth. Mechanistically, loss of Shp2 potentiates macrophage production of CXCL9 in response to IFN-γ and tumor cell-derived cytokines, thereby facilitating the tumor infiltration of IFN-γ-producing T cells that could in turn support CXCL9 production within tumor microenvironment. Collectively, our findings highlight a causative role of myeloid Shp2 in dampening T cell-mediated antitumor immunity by restraining the macrophage/CXCL9-T cell/IFN-γ feedback loop. Thus, targeting macrophage Shp2 may help to create a Th1-dominant tumor immune microenvironment.
Src 同源 2 结构域蛋白酪氨酸磷酸酶 2（Shp2）通常被认为是一种致癌基因，因为它能够增强多种类型肿瘤细胞的恶性程度；然而，其在调节肿瘤免疫方面的作用在很大程度上仍不清楚。在这里，我们报道了髓系细胞特异性 Shp2 缺失可抑制黑色素瘤的生长。在机制上，Shp2 的缺失增强了巨噬细胞对 IFN-γ 和肿瘤细胞来源的细胞因子的 CXCL9 产生，从而促进了 IFN-γ 产生的 T 细胞浸润，进而在肿瘤微环境中支持 CXCL9 的产生。总之，我们的研究结果强调了髓系细胞 Shp2 通过抑制巨噬细胞/CXCL9-T 细胞/IFN-γ 反馈环来抑制 T 细胞介导的抗肿瘤免疫的因果作用。因此，靶向巨噬细胞 Shp2 可能有助于创造 Th1 优势的肿瘤免疫微环境。
