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白细胞介素-10调节非小细胞肺癌中的肿瘤耐受性。

Interleukin-10-regulated tumour tolerance in non-small cell lung cancer.

作者信息

Vahl Julius Malte, Friedrich Juliane, Mittler Susanne, Trump Sonja, Heim Lisanne, Kachler Katerina, Balabko Liubov, Fuhrich Nicole, Geppert Carol-Immanuel, Trufa Denis Iulian, Sopel Nina, Rieker Ralf, Sirbu Horia, Finotto Susetta

机构信息

Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstraβe 14, Erlangen 91052, Germany.

Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Krankenhausstraβe 8-10, Erlangen 91054, Germany.

出版信息

Br J Cancer. 2017 Nov 21;117(11):1644-1655. doi: 10.1038/bjc.2017.336. Epub 2017 Oct 10.

DOI:10.1038/bjc.2017.336
PMID:29016555
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5729436/
Abstract

BACKGROUND

Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape.

METHODS

Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer.

RESULTS

Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3 T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis.

CONCLUSIONS

These new findings suggest that IL-10 counteracts IFN-γ effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.

摘要

背景

肺癌是全球最具生命威胁的癌症类型。治疗选择包括手术、放疗和化疗，以及使用免疫调节抗体。白细胞介素（IL）-10是一种参与肿瘤免疫逃逸的免疫抑制细胞因子。

方法

对人肺手术组织以及人肿瘤细胞系培养物进行免疫组织化学（IHC）、流式细胞术分析、实时PCR和实验性肺癌研究。

结果

在此，我们发现肺癌（非小细胞肺癌，全球最具生命威胁的癌症类型）患者肺中IL-10与IL-10受体（IL-10R）表达与肿瘤直径之间呈正相关。在肺肿瘤细胞周围的细胞中发现IL-10和IL-10R被诱导，并且IL-10R主要表达于浸润这些患者肿瘤的Foxp-3调节性T淋巴细胞表面，其表达与程序性细胞死亡蛋白1呈负相关。这些发现在转化研究中得到证实。在人肺腺癌细胞系中，发现IL-10R在肿瘤生长期间存在的代谢限制下被诱导，由此IL-10抑制程序性死亡受体配体1（PDL1）和肿瘤细胞凋亡。

结论

这些新发现表明IL-10抵消了干扰素-γ对程序性死亡蛋白1/程序性死亡受体配体1（PD1/PDL1）通路的作用，导致肿瘤可能对抗PD1/PDL1免疫疗法产生抗性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/b123028360ec/bjc2017336f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/453ed07c33b6/bjc2017336f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/5121d585e704/bjc2017336f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/954b2ab1804d/bjc2017336f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/29c2f329c705/bjc2017336f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/9aac526b18f7/bjc2017336f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/b123028360ec/bjc2017336f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/453ed07c33b6/bjc2017336f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/5121d585e704/bjc2017336f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/954b2ab1804d/bjc2017336f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/29c2f329c705/bjc2017336f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/9aac526b18f7/bjc2017336f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db80/5729436/b123028360ec/bjc2017336f6.jpg

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