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Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Interferon | Research

Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity

Authors: Lifeng Li, Li Yang, Shiqi Cheng, Zhirui Fan, Zhibo Shen, Wenhua Xue, Yujia Zheng, Feng Li, Dong Wang, Kai Zhang, Jingyao Lian, Dan Wang, Zijia Zhu, Jie Zhao, Yi Zhang

Published in: Molecular Cancer | Issue 1/2019

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Abstract

Background

Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD).

Methods

We used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo.

Results

GBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8+ T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo.

Conclusions

GBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8+ T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD.
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Metadata
Title
Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity
Authors
Lifeng Li
Li Yang
Shiqi Cheng
Zhirui Fan
Zhibo Shen
Wenhua Xue
Yujia Zheng
Feng Li
Dong Wang
Kai Zhang
Jingyao Lian
Dan Wang
Zijia Zhu
Jie Zhao
Yi Zhang
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Interferon
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-1027-x

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