免疫抑制性肿瘤浸润髓样细胞通过PD-1/PD-L1机制介导胶质母细胞瘤的适应性免疫抵抗。
Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma.
作者信息
Antonios Joseph P, Soto Horacio, Everson Richard G, Moughon Diana, Orpilla Joey R, Shin Namjo P, Sedighim Shaina, Treger Janet, Odesa Sylvia, Tucker Alexander, Yong William H, Li Gang, Cloughesy Timothy F, Liau Linda M, Prins Robert M
机构信息
Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
出版信息
Neuro Oncol. 2017 Jun 1;19(6):796-807. doi: 10.1093/neuonc/now287.
BACKGROUND
Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs).
METHODS
To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro.
RESULTS
Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation.
CONCLUSION
Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.
背景
肿瘤微环境中的适应性免疫抗性似乎会削弱胶质母细胞瘤（GBM）的免疫治疗靶向作用。在本研究中，我们鉴定出一种肿瘤浸润髓样细胞（TIM）群体，其会因树突状细胞（DC）疫苗治疗而扩增。本研究的目的是了解这个表达程序性死亡配体1（PD-L1）的群体如何限制疫苗诱导的肿瘤浸润淋巴细胞（TILs）的激活和肿瘤细胞溶解功能。
方法
为在我们的体内临床前模型中验证这一假设，我们用DC疫苗±鼠抗PD-1单克隆抗体（mAb）阻断剂或集落刺激因子1受体抑制剂（CSF-1Ri）（PLX3397）治疗患有颅内胶质瘤的小鼠，并测量总体生存期。然后我们收获并鉴定了PD-L1+ TIM群体及其在体外TIL激活和肿瘤细胞溶解中的作用。
结果
我们的数据表明，GBM环境中大部分的PD-L1表达是由TIMs而非肿瘤细胞自身产生的。虽然PD-1阻断部分逆转了TIL功能障碍，但用CSF-1Ri直接靶向TIMs改变了与促进疫苗接种后TIL浸润增加相关的关键趋化因子的TIM表达。单独使用PD-1 mAb或CSF-1Ri均未显示出明显的治疗益处，但与DC疫苗联合使用时，则观察到显著的生存益处。当给予三联方案（DC疫苗、PD-1 mAb、PLX3397）时，观察到长期生存以及TIL数量和TIL激活的增加。
结论
总之，这些研究阐明了TIMs在介导GBM微环境中的适应性免疫抗性中所起的作用，并提供了证据表明它们可以用临床可用药物进行药理学操纵。GBM中对主动疫苗接种产生的免疫抗性可通过联合使用CSF-1Ri和PD-1 mAb来逆转。
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