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Association between angiogenesis and cytotoxic signatures in the tumor microenvironment of gastric cancer

Authors Feng Y, Dai Y, Gong Z, Cheng JN, Zhang L, Sun C, Zeng X, Jia Q, Zhu B

Received 16 January 2018

Accepted for publication 9 March 2018

Published 10 May 2018 Volume 2018:11 Pages 2725—2733

DOI https://doi.org/10.2147/OTT.S162729

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Dr Ingrid Espinoza


Yi Feng,1,2 Ying Dai,1,2 Zhihua Gong,1,2 Jia-Nan Cheng,1,2 Longhui Zhang,1,2 Chengdu Sun,1,2 Xianghua Zeng,1,2 Qingzhu Jia,1,2 Bo Zhu1,2

1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing, People’s Republic of China

Background: A suppressive immune microenvironment and pathological angiogenesis are hallmarks of gastric cancer. Theoretically, immune checkpoint inhibitors (ICIs) stimulate pre-primed neoantigen-specific T cells, and antiangiogenic agents then facilitate their infiltration into the tumor niche by promoting vascular normalization. Currently, the interconnections of these two phenotypes and their relevance to the tumor microenvironment (TME) have not been fully characterized in gastric cancer.
Materials and methods: Transcriptome profiling data retrieved from The Cancer Genome Atlas (TCGA) database were used to deconvolute the feature of TME for gastric cancer (N = 375). Machine learning, correlation, and prognosis analysis were applied to elucidate the correlations between angiogenesis, cytotoxic T lymphocyte infiltration, and patient survival.
Results: Substantial heterogeneous infiltration of immune cell populations among cases was observed. Furthermore, among targetable pathways, angiogenesis was identified as the dominant factor in discriminating different infiltration statuses. Most importantly, the angiogenesis pathway was negatively correlated with the amount of activated CD8+ T cells only for patients with a higher infiltration, and the concomitance of low angiogenesis signaling and highly activated CD8+ T-cell infiltration was associated with a significant survival benefit.
Conclusion: Our findings demonstrated a negative correlation between angiogenesis signaling and cytotoxic function in gastric cancer patients with a highly infiltrated immune niche. These data provided a rationale for potential combination strategy and further clinical investigations of ICIs plus antiangiogenesis agents for patients with gastric cancer with an inflamed TME.

Keywords: gastric cancer, immune microenvironment, TCGA, angiogenesis, therapeutic implications

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