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Cytotoxic T lymphocyte antigen-4 (CTLA-4) expression in chordoma and tumor-infiltrating lymphocytes (TILs) predicts prognosis of spinal chordoma

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Abstract

Purpose

Chordoma is a rare tumor of the skeletal system that is characterized by a high recurrence rate and treatment resistance. Given the common finding of immune dysregulation in chordoma, immunotherapy has emerged as potential treatment option. As an important immune checkpoint regulator, we evaluated cytotoxic T-lymphocyte antigen-4 (CTLA-4) expression and its prognostic significance for patients with chordoma of the spine.

Methods

CTLA-4 expression was analyzed immunohistochemically in 32 chordoma tissues and 14 nucleus pulposus tissues to examine the specificity of CTLA-4 expression in chordoma. Univariate log-rank analysis was used to evaluate the association of CTLA-4 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) with survival. Cox multivariate analysis was used to identify independent factors of survival.

Results

Positive CTLA-4 expression was observed in all of the TILs and tumor cell cytoplasm, and partial in the membrane or in both the membrane and nucleus, with a markedly higher positivity rate than that observed in normal nucleus tissues. Higher CTLA-4 expression in the tumor but not in TILs was significantly associated with shorter continuous disease-free survival (CDFS) and overall survival (OS). CTLA-4 expression in tumor cells and TILs were independent predictors for CDFS, whereas only tumor cell expression was a significant predictor of OS. Furthermore, the combination of CTLA-4 expression in the tumor and TILs had higher prognostic value.

Conclusions

Targeting CTLA-4 may be a potential novel therapeutic strategy for chordoma patients.

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Abbreviations

CDFS:

Continuous disease-free survival

CTLA-4:

Cytotoxic T lymphocyte antigen 4

DAB:

Diaminobenzidine

FCEP:

Favorable CTLA-4 expression profile

IHC:

Immunohistochemistry

LSS:

Lumbar spinal stenosis

LDH:

Lumbar disk herniation

OS:

Overall survival

PD-1:

Programmed cell death protein 1

TILs:

Tumor-infiltrating lymphocytes

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Acknowledgements

We are grateful to the chordoma patients for donating their specimens for this study and to the surgery and nursing staff for assistance with sample collection. We also thank members of the Research Center of Peking University Third Hospital for providing technical support and assisting with the data analysis.

Funding

This study was partially funded by the National Natural Science Foundation of China (Grant No. 81802686) and Bei**g Natural Science Foundation (No. 7192226).

Author information

Authors and Affiliations

  1. Department of Orthopedics, North Garden Street, Peking University Third Hospital, No. 49, Haidian District, Bei**g, 100191, People’s Republic of China

    G. He, X. Liu, X. Pan & X. Liu

  2. The Center for Pain Medicine, North Garden Street, Peking University Third Hospital, No. 49, Haidian District, Bei**g, 100191, China

    Y. Ma

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Contributions

Conceived and designed the experiments: GH, XL. Performed the experiments: GH, XP, XL, YM. Analyzed the data: GH, XP, XL, XL. Wrote the paper: GH, XL.

Corresponding author

Correspondence to X. Liu.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the ethics committee of Peking University Third Hospital (No. IRB00006761-2016048).

Consent to participate

Informed consent for use of their specimens and data in this study was obtained from all adult patients or written parental consent was provided for minors before the study was conducted.

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The data and materials are available from the corresponding author on reasonable request.

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He, G., Liu, X., Pan, X. et al. Cytotoxic T lymphocyte antigen-4 (CTLA-4) expression in chordoma and tumor-infiltrating lymphocytes (TILs) predicts prognosis of spinal chordoma. Clin Transl Oncol 22, 2324–2332 (2020). https://doi.org/10.1007/s12094-020-02387-7

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