Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer.
Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer.
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PD-1/PD-L1检查点激活需要髓样细胞，并在胰腺癌中建立免疫抑制环境。
DOI：
10.1136/gutjnl-2016-312078
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发表时间：
2017-01
期刊：
影响因子：
24.5
通讯作者：
Pasca di Magliano M
中科院分区：
文献类型：
--
作者：
Zhang Y;Velez-Delgado A;Mathew E;Li D;Mendez FM;Flannagan K;Rhim AD;Simeone DM;Beatty GL;Pasca di Magliano M
胰腺癌的特征在于纤维炎性基质的积累。在这种基质反应中，髓样细胞是主要群体。不同的骨髓亚群与肿瘤促进和抗肿瘤免疫的暴露相关。本研究的目的是确定骨髓细胞耗竭对胰腺癌发病和进展的影响，并了解胰腺癌微环境中骨髓细胞和T细胞介导的免疫之间的关系。将原代小鼠胰腺癌细胞移植到CD 11b-白喉毒素受体（DTR）小鼠中。或者，将胰腺癌的iKras* 小鼠模型与CD 11b-DTR小鼠杂交。CD 11b+细胞（主要是骨髓细胞群）在肿瘤发生或已建立的肿瘤中被白喉毒素治疗耗尽。骨髓细胞的耗竭阻止了KrasG 12 D驱动的胰腺癌的发生。在预先建立的肿瘤中，骨髓细胞耗竭阻止了肿瘤生长，在某些情况下，诱导了依赖于CD 8 + T细胞的肿瘤消退。我们发现骨髓细胞通过诱导肿瘤细胞中程序性细胞死亡配体1（PD-L1）以表皮生长因子受体（EGFR）/丝裂原活化蛋白激酶（MAPK）依赖性方式表达来抑制CD 8 + T细胞抗肿瘤活性。我们的研究结果表明，骨髓细胞通过EGFR/MAPK依赖性调节肿瘤细胞上PD-L1表达来支持胰腺癌的免疫逃避。使骨髓细胞和肿瘤细胞之间的这种串扰偏离足以恢复由CD 8 + T细胞介导的抗肿瘤免疫，这一发现对胰腺癌免疫疗法的设计具有意义。
Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity. The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment. Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours. Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner. Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.