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Clinical and Translational Oncology

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01-12-2020 | Research Article

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

Authors: G. He, X. Liu, X. Pan, Y. Ma, X. Liu

Published in: Clinical and Translational Oncology | Issue 12/2020

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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Matsumoto T, Imagama S, Ito Z, Imai R, Kamada T, Shimoyama Y, Matsuyama Y, Ishiguro N. Total spondylectomy following carbon ion radiotherapy to treat chordoma of the mobile spine. Bone Joint J. 2013;95(10):1392–5.PubMed

Park L, Delaney TF, Liebsch NJ, Hornicek FJ, Goldberg S, Mankin H, Rosenberg AE, Rosenthal DI, Suit HD. Sacral chordomas: impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor. Int J Radiat Oncol Biol Phys. 2006;65(5):1514–21.PubMed

Tzortzidis F, Elahi F, Wright D, Natarajan SK, Sekhar LN. Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Neurosurgery. 2006;59(2):230–7.PubMed

Kayani B, Hanna SA, Sewell MD, Saifuddin A, Molloy S, Briggs TW. A review of the surgical management of sacral chordoma. Eur J Surg Oncol. 2014;40(11):1412–20.PubMed

Patel SS, Schwab JH. Immunotherapy as a potential treatment for chordoma: a review. Curr Oncol Rep. 2016;18(9):55.PubMed

Bordon Y. Immunotherapy: Checkpoint parley. Nat Rev Cancer. 2015;15(1):3.PubMed

Thomas A, Hassan R. CTLA-4 blockade in mesothelioma: ineffective or reason for optimism? Lancet Oncol. 2017;18(9):1150–1.PubMed

Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, Izzeddine H, Marabelle A, Champiat S, Berdelou A, Lanoy E, Texier M, Libenciuc C, Eggermont AM, Soria JC, Mateus C, Robert C. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473–86.PubMed

Migliorini D, Mach N, Aguiar D, Vernet R, Landis BN, Becker M, McKee T, Dutoit V, Dietrich PY. First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies. Oncoimmunology. 2017;6(8):e1338235.PubMedPubMedCentral

10.

Feng Y, Shen J, Gao Y, Liao Y, Cote G, Choy E, Chebib I, Mankin H, Hornicek F, Duan Z. Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma. Oncotarget. 2015;6(13):11139–49.PubMedPubMedCentral

11.

Feng Y, Shen J, Gao Y, Liao YG, Cote G, Choy E, Chebib I, Mankin H, Hornicek F, Duan ZG. Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-in ltrating lymphocytes (TILs) in chordoma. Oncotarget. 2015;6(13):11139–49.PubMedPubMedCentral

12.

Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily–CTLA-4. Nature. 1987;328(6127):267–70.

13.

Greenwald RJ, Latchman YE, Sharpe AH. Negative co-receptors on lymphocytes. Curr Opin Immunol. 2002;14(3):391–6.PubMed

14.

Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002;2(2):116–26.PubMed

15.

Mittal AK, Chaturvedi NK, Rohlfsen RA, Gupta P, Joshi AD, Hegde GV, Bociek RG, Joshi SS. Role of CTLA4 in the proliferation and survival of chronic lymphocytic leukemia. PLoS ONE. 2013;8(8):e70352.PubMedPubMedCentral

16.

Menon S, Shin S, Dy G. Advances in cancer immunotherapy in solid tumors. Cancers (Basel). 2016. https://doi.org/10.3390/cancers8120106.CrossRefPubMedCentral

17.

Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J. Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer Immunol Immunother. 2015;64(7):853–60.PubMedPubMedCentral

18.

Huang PY, Guo SS, Zhang Y, Lu JB, Chen QY, Tang LQ, Zhang L, Liu LT, Zhang L, Mai HQ. Tumor CTLA-4 overexpression predicts poor survival in patients with nasopharyngeal carcinoma. Oncotarget. 2016;7(11):13060–8.PubMedPubMedCentral

19.

Santoni G, Amantini C, Morelli MB, Tomassoni D, Santoni M, Marinelli O, Nabissi M, Cardinali C, Paolucci V, Torniai M, Rinaldi S, Morgese F, Bernardini G, Berardi R. High CTLA-4 expression correlates with poor prognosis in thymoma patients. Oncotarget. 2018;9(24):16665–777.PubMedPubMedCentral

20.

Roncella S, Laurent S, Fontana V, Ferro P, Franceschini MC, Salvi S, Varesano S, Boccardo S, Vigani A, Morabito A, Canessa PA, Giannoni U, Rosenberg I, Valentino A, Fedeli F, Merlo DF, Ceppi M, Riggio S, Romani M, Saverino D, Poggi A, Pistillo MP. CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor. Cancer Immunol Immunother. 2016;65(8):909–17.PubMed

21.

Salvi S, Fontana V, Boccardo S, Merlo DF, Margallo E, Laurent S, Morabito A, Rijavec E, Dal Bello MG, Mora M, Ratto GB, Grossi F, Truini M, Pistillo MP. Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer. Cancer Immunol Immunother. 2012;61(9):1463–72.PubMed

22.

Samson IR, Springfield DS, Suit HD, Mankin HJ. Operative treatment of sacrococcygeal chordoma. A review of twenty-one cases. J Bone Joint Surg Am. 1993;75(10):1476–84.PubMed

23.

Meng T, Yin H, Li B, Li Z, Xu W, Zhou W, Cheng M, Wang J, Zhou L, Yang X, Liu T, Yan W, Song D, Xiao J. Clinical features and prognostic factors of patients with chordoma in the spine: a retrospective analysis of 153 patients in a single center. Neuro Oncol. 2015;17(5):725–32.PubMed

24.

Zhang XF, Pan K, Weng DS, Chen CL, Wang QJ, Zhao JJ, Pan QZ, Liu Q, Jiang SS, Li YQ, Zhang HX, Xia JC. Cytotoxic T lymphocyte antigen-4 expression in esophageal carcinoma: implications for prognosis. Oncotarget. 2016;7(18):26670–9.PubMedPubMedCentral

25.

Walcott BP, Nahed BV, Mohyeldin A, Coumans JV, Kahle KT, Ferreira MJ. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69–76.PubMed

26.

Zou MX, Lv GH, Wang XB, Li J. Letter: factors predicting recurrence after resection of clival chordoma using variable surgical approaches and radiation modalities. Neurosurgery. 2017;81(2):E28–E31.PubMed

27.

Ferraresi V, Nuzzo C, Zoccali C, Marandino F, Vidiri A, Salducca N, Zeuli M, Giannarelli D, Cognetti F, Biagini R. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer. 2010;10:22.PubMedPubMedCentral

28.

Paulsen EE, Kilvaer TK, Rakaee M, Richardsen E, Hald SM, Andersen S, Busund LT, Bremnes RM, Donnem T. CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases. Cancer Immunol Immunother. 2017;66(11):1449–611.PubMedPubMedCentral

29.

Zhao Y, Yang W, Huang Y, Cui R, Li X, Li B. Evolving roles for targeting CTLA-4 in cancer immunotherapy. Cell Physiol Biochem. 2018;47(2):721–34.PubMed

30.

Wang C, Xu L, Liang C, Xiang J, Peng R, Liu Z. Immunological responses triggered by photothermal therapy with carbon nanotubes in combination with anti-CTLA-4 therapy to inhibit cancer metastasis. Adv Mater. 2014;26(48):8154–62.PubMed

31.

Smyth MJ, Yagita H, McArthur GA. Combination anti-CTLA-4 and anti-RANKL in metastatic melanoma. J Clin Oncol. 2016;34(12):e104–e106106.PubMed

32.

Erfani N, Mehrabadi SM, Ghayumi MA, Haghshenas MR, Mojtahedi Z, Ghaderi A, Amani D. Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC). Lung Cancer. 2012;77(2):306–11.PubMed

33.

Kim JW, Nam KH, Ahn SH, Park DJ, Kim HH, Kim SH, Chang H, Lee JO, Kim YJ, Lee HS, Kim JH, Bang SM, Lee JS, Lee KW. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2016;19(1):42–52.PubMed

Title: Cytotoxic T lymphocyte antigen-4 (CTLA-4) expression in chordoma and tumor-infiltrating lymphocytes (TILs) predicts prognosis of spinal chordoma
Authors: G. He
X. Liu
X. Pan
Y. Ma
X. Liu
Publication date: 01-12-2020
Publisher: Springer International Publishing
Published in: Clinical and Translational Oncology / Issue 12/2020
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-020-02387-7

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Abstract

Purpose

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