Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
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DOI：
10.1158/1078-0432.ccr-18-2402
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发表时间：
2019-06-15
影响因子：
11.5
通讯作者：
Bloch, Orin
中科院分区：
文献类型：
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作者：
Lamano, Jonathan B.;Lamano, Jason Balquidera;Bloch, Orin
目的：循环和肿瘤浸润性骨髓细胞上程序性死亡配体1（PD-L1）的上调是GBM介导的免疫抑制的关键组成部分，与疫苗免疫治疗反应减弱和生存期差有关。虽然GBM衍生的可溶性因子与髓样PD-L1表达有关，但这些因子的身份仍然未知。本研究旨在确定负责髓样PD-L1上调的因素作为免疫modulation.Experimental设计的潜在目标：条件培养基从患者来源的GBM外植体细胞培养物进行了评估细胞因子的表达，并用于刺激幼稚髓样细胞。通过流式细胞术定量髓样PD-L1诱导。在肿瘤切片和血浆中评价与PD-L1诱导相关的候选细胞因子与存活率和骨髓PD-L1表达的关系。利用具有免疫活性的C57 BL/6小鼠携带同基因GL 261和CT-2A tumors.Results：GBM衍生的IL 6被鉴定为通过STAT 3依赖性机制在GBM中对髓样PD-L1诱导是必要且充分的细胞因子。原位鼠胶质瘤模型中IL 6信号传导的抑制与髓样PD-L1表达降低、肿瘤生长减少和存活增加相关。抗IL-6治疗的益处被证明是CD 8（+）T细胞依赖性的，并且抗肿瘤活性与程序性死亡-1（PD-1）靶向免疫疗法提供的抗肿瘤活性是相加的。结论：我们的研究结果表明，GBM中IL-6信号传导的破坏减少了局部和全身骨髓驱动的免疫抑制，并增强了针对GBM的免疫介导的抗肿瘤反应。
Purpose: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.Experimental Design: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naive myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.Results: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8(+) T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.Conclusions: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated anti-tumor responses against GBM.