GM-CSF mediates immune evasion via upregulation of PD-L1 expression in extranodal natural killer/T cell lymphoma.
GM-CSF mediates immune evasion via upregulation of PD-L1 expression in extranodal natural killer/T cell lymphoma.
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DOI：
10.1186/s12943-021-01374-y
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发表时间：
2021-05-29
期刊：
影响因子：
37.3
通讯作者：
Fu LW
中科院分区：
文献类型：
--
作者：
Rong QX;Wang F;Guo ZX;Hu Y;An SN;Luo M;Zhang H;Wu SC;Huang HQ;Fu LW
粒细胞巨噬细胞集落刺激因子（GM-CSF）是近年来被用作抗肿瘤治疗的免疫增强剂的细胞因子。我们发现，一些接受 hGM-CSF 治疗的结外自然杀伤/T 细胞淋巴瘤 (ENKTL) 患者迅速出现疾病进展，但其潜在机制仍有待阐明。在这里，我们的目的是探讨 GM-CSF 在 ENKTL 中引发疾病进展的机制。建立EL4细胞瘤小鼠模型，研究GM-CSF对肿瘤生长、T细胞浸润和功能的影响。使用包括NK-YS、SNK-6和SNT-8在内的人ENKTL细胞系来探讨GM-CSF诱导的程序性死亡配体1（PD-L1）的表达。为了进一步详细研究ENKTL疾病进展的机制，通过下一代序列（NGS）检查ENKTL患者肿瘤组织样本中的突变和基因表达谱。与用 IgG 或 GM-CSF 和 PD-1 抗体组合治疗相比，单独用 GM-CSF 治疗的小鼠 EL4 细胞肿瘤表现出更快的肿瘤生长速度和更差的存活率。在用 GM-CSF 处理的 ENKTL 细胞中，PD-L1 mRNA 和蛋白质水平的表达显着增加。在12例ENKTL病例的基线组织样本中发现STAT5A高频突变，包括p.R131G、p.D475N、p.F706fs、p.V707E和p.S710F。重要的是，STAT5A-V706fs 突变肿瘤细胞在 GM-CSF 存在下表现出 STAT5A 通路激活增加和 PD-L1 过表达。这些发现表明，GM-CSF可能会引发ENKTL患者肿瘤免疫监视的丧失并促进疾病进展，这与STAT5突变和JAK2过度磷酸化有关，然后上调PD-L1的表达。这些可能为GM-CSF的应用提供新理念，为ENKTL的治疗提供新策略。在线版本包含可在 10.1186/s12943-021-01374-y 获取的补充材料。
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine that is used as an immunopotentiator for anti-tumor therapies in recent years. We found that some of the extranodal natural killer/T cell lymphoma (ENKTL) patients with the treatment of hGM-CSF rapidly experienced disease progression, but the underlying mechanisms remain to be elucidated. Here, we aimed to explore the mechanisms of disease progression triggered by GM-CSF in ENKTL. The mouse models bearing EL4 cell tumors were established to investigate the effects of GM-CSF on tumor growth and T cell infiltration and function. Human ENKTL cell lines including NK-YS, SNK-6, and SNT-8 were used to explore the expression of programmed death-ligand 1 (PD-L1) induced by GM-CSF. To further study the mechanisms of disease progression of ENKTL in detail, the mutations and gene expression profile were examined by next-generation sequence (NGS) in the ENKTL patient’s tumor tissue samples. The mouse-bearing EL4 cell tumor exhibited a faster tumor growth rate and poorer survival in the treatment with GM-CSF alone than in treatment with IgG or the combination of GM-CSF and PD-1 antibody. The PD-L1 expression at mRNA and protein levels was significantly increased in ENKTL cells treated with GM-CSF. STAT5A high-frequency mutation including p.R131G, p.D475N, p.F706fs, p.V707E, and p.S710F was found in 12 ENKTL cases with baseline tissue samples. Importantly, STAT5A-V706fs mutation tumor cells exhibited increased activation of STAT5A pathway and PD-L1 overexpression in the presence of GM-CSF. These findings demonstrate that GM-CSF potentially triggers the loss of tumor immune surveillance in ENKTL patients and promotes disease progression, which is associated with STAT5 mutations and JAK2 hyperphosphorylation and then upregulates the expression of PD-L1. These may provide new concepts for GM-CSF application and new strategies for the treatment of ENKTL. The online version contains supplementary material available at 10.1186/s12943-021-01374-y.
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影响因子：
20.3
作者：
Drenou, B;Lamy, T;Fauchet, R
通讯作者：
Fauchet, R
影响因子：
15.9
作者：
Jinushi, Masahisa;Nakazaki, Yukoh;Dranoff, Glenn
通讯作者：
Dranoff, Glenn
影响因子：
10.9
作者：
Andtbacka, Robert H., I;Collichio, Frances;Kaufman, Howard L.
通讯作者：
Kaufman, Howard L.
影响因子：
10.1
作者：
Luke, Jason J.;Donahue, Hilary;Hodi, F. Stephen
通讯作者：
Hodi, F. Stephen
DOI：
10.1016/s1470-2045(16)30364-3
发表时间：
2016-10
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Kaufman HL;Russell J;Hamid O;Bhatia S;Terheyden P;D'Angelo SP;Shih KC;Lebbé C;Linette GP;Milella M;Brownell I;Lewis KD;Lorch JH;Chin K;Mahnke L;von Heydebreck A;Cuillerot JM;Nghiem P
通讯作者：
Nghiem P