UNC Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Center for Integrative Chemical Biology and Drug Discovery, Division for Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Cancer Immunol Res. 2019 Oct;7(10):1672-1686. doi: 10.1158/2326-6066.CIR-19-0008. Epub 2019 Aug 26.
Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing , and mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3, AXL, and MERTK MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs Consistent with these findings, pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8 T-cell infiltration, and augmented anti-PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK and TYRO3 M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL, and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients.
髓系细胞受体酪氨酸激酶 TYRO3、AXL 和 MERTK 及其配体 GAS6 和 PROTEIN S 在生理上抑制固有免疫反应，包括肿瘤微环境中的固有免疫反应。在这里，我们表明，髓系来源的抑制细胞 (MDSC) 在荷瘤小鼠中显著上调 TYRO3、AXL 和 MERTK 及其配体[单核细胞 MDSC (M-MDSC)>20 倍，多形核 MDSC (PMN-MDSC)>15 倍]。来自荷瘤小鼠的 MDSC 表现出抑制酶活性降低，T 细胞抑制缺陷，并且向肿瘤引流淋巴结迁移不良。在使用 TYRO3、AXL 和 MERTK MDSC 的共植入实验中，我们表明这些 RTK 的缺失逆转了 MDSC 的促肿瘤特性。与这些发现一致，药理抑制 TYRO3、AXL 和 MERTK 降低了 MDSC 的抑制能力，减缓了肿瘤生长，增加了 CD8 T 细胞浸润，并增强了抗 PD-1 检查点抑制剂免疫治疗。在机制上，MERTK 通过调节 STAT3 丝氨酸磷酸化和核定位部分调节 MDSC 的抑制和分化。对转移性黑色素瘤患者的分析表明，与健康对照组相比，循环中存在更多的 MERTK 和 TYRO3 M-MDSC、PMN-MDSC 和早期 MDSC (e-MDSC)。这些研究表明，TYRO3、AXL 和 MERTK 控制 MDSC 的功能，是调节癌症患者 MDSC 介导的免疫抑制的有前途的药理靶点。
