Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression.
Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression.
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DOI：
10.1158/1541-7786.mcr-16-0350
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Birge RB
中科院分区：
文献类型：
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作者：
Kasikara C;Kumar S;Kimani S;Tsou WI;Geng K;Davra V;Sriram G;Devoe C;Nguyen KN;Antes A;Krantz A;Rymarczyk G;Wilczynski A;Empig C;Freimark B;Gray M;Schlunegger K;Hutchins J;Kotenko SV;Birge RB
Tyro3、Ax1和MerTK(统称为受体)是三种同源受体酪氨酸激酶(RTK)，它们与依赖维生素K的内源性配体S(Pros)和生长抑制特定因子6(Gas6)结合，并作为桥梁分子促进磷脂酰丝氨酸(PS)介导的细胞凋亡清除(泡沫化)。受体在多种肿瘤类型中都有过表达，其表达水平与肿瘤分级、靶向治疗出现化疗和放射耐药有关，但也被认为是肿瘤微环境中侵袭髓系细胞的抑制受体，从而抑制宿主的抗肿瘤免疫。在本研究中，我们利用-干扰素γR1报告系，并在多种上皮细胞模型系统中表达受体，表明每个受体都有独特的被Gas6或PRO激活的模式，以及对PS依赖于凋亡细胞和PS脂质体的独特活性。此外，我们利用这个系统对表达WT受体的上皮细胞进行了工程，结果表明，虽然每个受体都可以促进PS介导的胞吐、AKT介导的化疗耐药以及上调肿瘤细胞上的免疫检查点分子PD-L1，但MerTK在上述途径中占主导地位。在功能上，受体介导的胞吐作用可被PS靶向抗体11.31和Annexin V部分阻断，表明存在PS/PS受体(即受体)/PD-L1轴，该轴作用于上皮细胞，促进免疫逃逸。这些数据为PS靶向、抗受体和抗PD-L1治疗药物作为联合检查点抑制剂提供了理论基础。
Tyro3, Axl and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases (RTKs) that bind vitamin K-dependent endogenous ligands, Protein S (ProS) and Growth arrest specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radio-resistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment (TME) that can suppress host anti-tumor immunity. In the present study, we utilized TAM-IFNγR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express WT TAM receptors, and show that while each receptor can promote PS-mediated efferocytosis, AKT-mediated chemo-resistance, as well as up-regulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor-mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 and Annexin V, demonstrating the existing of a PS/PS-Receptor (i.e. TAM-receptor) /PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti-TAM receptor, and anti-PD-L1 based therapeutics will have merit as combinatorial checkpoint inhibitors.