Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8(+) T cell exclusion.
Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8(+) T cell exclusion.
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颗粒体蛋白前体通过上调肿瘤相关巨噬细胞 (TAM) 上的 PD-L1 表达并促进 CD8( ) T 细胞排斥来诱导乳腺癌免疫逃逸
DOI：
10.1186/s13046-020-01786-6
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发表时间：
2021-01-04
期刊：
影响因子：
--
通讯作者：
Chen T
中科院分区：
文献类型：
--
作者：
Fang W;Zhou T;Shi H;Yao M;Zhang D;Qian H;Zeng Q;Wang Y;Jin F;Chai C;Chen T
前颗粒蛋白（proanulin， PGRN）是一种多功能生长因子，在多种肿瘤中过表达，但其在肿瘤免疫中的作用尚不清楚。本文研究PGRN对乳腺癌肿瘤免疫的影响及其可能的分子机制。采用western blot、定量聚合酶链反应（PCR）和流式细胞术检测PGRN对巨噬细胞表型的影响。Western blot方法研究PGRN调控这一过程的信号分子机制。采用免疫组织化学染色和免疫荧光技术分析野生型（WT）和PGRN - / -乳腺癌组织中免疫细胞的数量和定位。流式细胞术检测CD8+ T细胞的活化和增殖情况。经PGRN处理后，巨噬细胞M2标记物和程序性死亡配体1 （PD-L1）的表达明显升高。STAT3信号通路抑制剂Stattic显著抑制PGRN诱导的PD-L1和M2相关标志物的表达。在WT组，CD8与巨噬细胞和PD-L1共定位，但不与肿瘤细胞共定位。PGRN−/−乳腺癌组织中免疫细胞数量增加，向肿瘤实质浸润增强。此外，在共培养体系中，WT腹膜巨噬细胞不仅降低了活化CD8+ T细胞的比例，而且降低了增殖CD8+ T细胞的比例。程序性死亡受体1 （PD-1）和PD-L1中和抗体的加入有效地逆转了这种作用，恢复了CD8+ T细胞的免疫功能。这些结果表明PGRN通过激活STAT3信号通路促进M2极化和PD-L1表达。此外，PGRN通过PD-1/PD-L1相互作用促进乳腺肿瘤免疫逃逸。我们的研究可能为临床乳腺癌免疫治疗提供新的思路和靶点。在线版本包含补充材料，可在10.1186/s13046-020-01786-6获得。
Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism. The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN−/− breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry. After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN−/− breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells. These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy. The online version contains supplementary material available at 10.1186/s13046-020-01786-6.
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DOI：
10.1073/pnas.1720948115
发表时间：
2018-04-24
影响因子：
11.1
作者：
Peranzoni E;Lemoine J;Vimeux L;Feuillet V;Barrin S;Kantari-Mimoun C;Bercovici N;Guérin M;Biton J;Ouakrim H;Régnier F;Lupo A;Alifano M;Damotte D;Donnadieu E
通讯作者：
Donnadieu E
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
促生蛋白：一种生长因子，一种新型的TNFR配体和药物靶标。
影响因子：
13.5
作者：
Liu, Chuan-ju;Bosch, Xavier
通讯作者：
Bosch, Xavier
影响因子：
4.4
作者：
Li, Piao;Huang, Tingting;Qiu, Hong
通讯作者：
Qiu, Hong