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FUT4 is involved in PD-1-related immunosuppression and leads to worse survival in patients with operable lung adenocarcinoma

Journal of Cancer Research and Clinical Oncology volume 145, pages 65–76 (2019)Cite this article

Abstract

Purpose

As an important glycosyltransferase, fucosyltransferase IV (FUT4) is abnormally upregulated in different types of cancers, but its clinical role remains inexplicit. This work aimed to determine the predictive ability of FUT4 in lung adenocarcinoma (LUAD) after curative resection, as well as to explore the role of a possible FUT4 molecular mechanism on LUAD malignant behavior.

Methods

A total of 273 LUAD patients after curative resection with complete clinicopathological and RNAseq data from The Cancer Genome Atlas (TCGA) cohort were collected. Correlation of FUT4 with overall survival (OS) was analyzed based on TCGA and further validated by online “Kaplan–Meier Plotter” database and IHC in 70 LUAD patients recruited in the First Hospital of China Medical University cohort. Multivariate Cox regression analysis and 1000 bootstrapping were performed to verify the predictive value of FUT4. Gene set enrichment assay (GSEA) was performed to investigate the biological characteristics. Correlation between PD-1 and FUT4 was analyzed based on TCGA cohort and validated by IHC on cohort from our hospital.

Results

Increased FUT4 expression led to reduced overall survival (OS) of LUAD patients based on TCGA (p = 0.006 and 0.001 for dichotomous and trichotomous modeling, respectively) and externally validated in KMPLOTTER (p = 0.01) and by IHC based on cohort from our hospital (p = 0.005 and p = 0.019 for dichotomous and trichotomous modeling, respectively). FUT4 overexpression was an independent high risk factor for OS along with advanced pT stage and pTNM stage (p = 0.001, p = 0.037, and p < 0.001, respectively). GSEA revealed that FUT4 overexpression might correlate with shortened survival of LUAD patients by promoting cell proliferation via ERBB signaling, and suppressing immune response-related pathways. FUT4 expression positively correlated with PD-1 in TCGA (p = 0.026) and validated by IHC on cohort from our hospital (p = 0.029).

Conclusions

Increased FUT4 expression led to reduced OS in operable LUAD. FUT4 showed significant correlation with immune response and PD-1 expression.

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Acknowledgements

We thank Huihui Xu for her technical support. This work was supported by National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2017ZX09304025), the National Key Research and Development Program of China (No. 2017YFC1308900), Distinguished Professor of Liaoning Province, Science and Technology Plan Project of Liaoning Province (Nos. 2016007010, 2015020457), Foundation for selected Overseas Chinese Scholar 2015, the general project of Liaoning Province department of education (No. LZ2015073), and the Key Research and Development Program of Shenyang (No. 17-230-9-01).

Funding

This work was supported by National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2017ZX09304025), the National Key Research and Development Program of China (No. 2017YFC1308900), Distinguished Professor of Liaoning Province, Science and Technology Plan Project of Liaoning Province (No. 2016007010, 2015020457), Foundation for selected Overseas Chinese Scholar 2015, the general project of Liaoning Province department of education (No. LZ2015073), and the Key Research and Development Program of Shenyang (No. 17-230-9-01).

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  1. Chang Liu and Zhi Li are co-first authors of this article.

Affiliations

  1. Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China

    Chang Liu, Zhi Li, Shuo Wang, Yibo Fan, Simeng Zhang, Kezuo Hou, Xiaonan Shi, Xiaoxun Wang, Yunpeng Liu, Xiaofang Che & Xiujuan Qu

  2. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China

    Chang Liu, Zhi Li, Shuo Wang, Yibo Fan, Simeng Zhang, Kezuo Hou, Xiaonan Shi, Xiaoxun Wang, Yunpeng Liu, Xiaofang Che & Xiujuan Qu

  3. Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Xianghong Yang

  4. Medical Research Center, The Fourth Hospital of China Medical University, Shenyang, 110032, China

    Chang Liu

  5. Drug Clinical Trial Institution, The First Hospital of China Medical University, Shenyang, 110001, China

    Jianhua Tong

  6. Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, 110001, China

    Xuejun Hu

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  1. Chang Liu
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Ethics Committee of the First Hospital of China Medical University approved the project and the study number of IRB approval is 2014-2014-25-2.

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Fig. S1

. The flowchart of TCGA patient screening. (TIF 587 KB)

Fig. S2

. Time-dependent ROC analysis for the CPPs, and the combination of FUT4 and CPPs. (TIF 282 KB)

Fig. S3

. Nomogram and calibration for predicting 1- and 3-year OS of LUAD patients were shown. A. To calculate the 1- and 3-year survival, first determine the value for each factor by drawing a vertical line from that factor to the points scale. Then sum up all the individual points and draw a vertical line from the total points scale to the probability at the 1- and 3-year survival lines. B. 1-year and C. 3-year nomogram calibration curve of the nomogram were plotted. (TIF 1141 KB)

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Liu, C., Li, Z., Wang, S. et al. FUT4 is involved in PD-1-related immunosuppression and leads to worse survival in patients with operable lung adenocarcinoma. J Cancer Res Clin Oncol 145, 65–76 (2019). https://doi.org/10.1007/s00432-018-2761-y

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Keywords

  • FUT4
  • Lung adenocarcinoma
  • PD-1
  • Prognosis
  • Survival