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Clinicopathological implications of TIM3+ tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients

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Abstract

Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan–Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.

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Abbreviations

ATCC:

American Type Culture Collection

C-Cbl:

C-Casitas B lineage lymphoma

CD8:

Cluster of differentiation 8

CT:

Computed tomography

CTLA-4:

Cytolytic T lymphocyte-associated Ag-4

Gal9:

Galectin-9

HE:

Hematoxylin and eosin

KPS:

Karnofsky performance status

LRFS:

Local recurrence-free survival

MiRNAs:

MicroRNAs

NC:

Negative control

qPCR:

Quantitative real-time polymerase chain reaction

SOX9:

Sex-determining region Y (SRY)-box 9

TIM3:

T-cell immunoglobulin and mucin-domain 3

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81101917, 81270036, 30901736), the Liaoning Province Natural Science Foundation (No. 20170541022), the Plan to Focus on Research and Development from Science and Technology project of Liaoning Province (No. 2017225029), the Science and Technology Plan Project of Shenyang City (No. 18-014-4-11), and the Fund for Scientific Research of The First Hospital of China Medical University (No. FHCMU-FSR).

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Author notes

  1. Jinpeng Zhou and Yang Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China

    Jinpeng Zhou, Yang Jiang, Lian Chen, Peng Luo, Long Li, Junshuang Zhao & Zhitao Jing

  2. Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China

    Yang Jiang

  3. International Education College, Liaoning University of Traditional Chinese Medicine, No. 79, Chongshan East Road, Huanggu District, Shenyang, 110032, China

    Haiying Zhang

  4. The First Laboratory of Cancer Institute, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China

    Fei Lv, Dan Zou & Ye Zhang

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  1. Jinpeng Zhou
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Contributions

ZJ and YZ conceived and designed the study; JZ and YJ performed the experiments and collected the data; HZ, JZ, LC, PL, LL, JZ, and YJ produced the figures and tables; all authors performed the analysis and analyzed the data. JZ, YJ, YZ, and ZJ interpreted results and wrote the manuscript. FL, DZ, and HZ modified the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Ye Zhang or Zhitao Jing.

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Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

The study was approved by the Research Ethics Committee of the First Hospital of China Medical University and was in accordance with the ethical standards of the institutional committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study approval number is AF-SOP-07-01.

Informed consent

Informed consent was obtained from all individual participants included in the study. With approval from the National Science Foundation of China (81101917), we designed informed consent forms that were signed by eligible patients before recruitment into the study and admission to the hospital. The patients agreed to the use of their specimens and clinical data for research purposes only.

Cell line authentication

The human chordoma cell line UM-Chor1 was obtained as a gift from Professor Yazhuo Zhang, Department of Neurosurgery, Beijing Tiantan Hospital. The origin of UM-Chor1 was human clivus chordoma tissue. The American Type Culture Collection (ATCC) performed authentication of cell line UM-Chor1 via cytochrome C oxidase I assay and short tandem repeat analysis. We obtained a cell line authentication certificate from the ATCC.

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Zhou, J., Jiang, Y., Zhang, H. et al. Clinicopathological implications of TIM3+ tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients. Cancer Immunol Immunother 68, 1157–1169 (2019). https://doi.org/10.1007/s00262-019-02349-1

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  • DOI: https://doi.org/10.1007/s00262-019-02349-1

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