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Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy

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Abstract

Objectives

Advanced age and female sex have been associated with worse outcomes in patients undergoing radical cystectomy for muscle-invasive bladder cancer. A reduced immune response has been implicated as a mechanism. The objective of our study was to analyze the expression patterns of various cellular proteins active in bladder cancer immune pathways, and assess the correlation between age, sex, and the expression of these immune markers.

Methods

We obtained surgical tissue samples from equally distributed male/female patients with/without lymph node metastasis who had undergone radical cystectomy for urothelial carcinoma (UC) of the bladder (n = 50). Immunohistochemistry (IHC) for CD3 (cluster of differentiation), CD4, CD8, CD56, LAG-3 (lymphocyte-activation gene), TIM-3 (T-cell immunoglobulin and mucin-domain), PD-1 (programmed death) and PD-L1 molecules was performed and scored by a single pathologist (high versus low). Spearman’s correlation and Chi square tests investigated the association between age, sex, and IHC results.

Results

Mean age at surgery was 67 years (range 50–78 years); all patients were Caucasians. The following percent of patients scored high for a stain: 18% CD3, 10% CD4, 0% CD8, 0% CD56, 20% LAG-3, 4% TIM-3, 0% PD-1 and 0% PD-L1. There was no association between patients’ age, sex, and the expression of any of the immune markers (p > 0.05 for all).

Conclusions

The association between advanced age, female sex, and worse outcomes in bladder cancer may be independent of the immune pathways active in the disease that we examined in this study.

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Abbreviations

CD:

Cluster of differentiation

IHC:

Immunohistochemistry

LAG-3:

Lymphocyte-activation gene 3

PD-1:

Programmed death receptor 1

PD-L1:

Programmed death receptor ligand 1

SEER:

Surveillance, Epidemiology and End Results program

TIM-3:

T-cell immunoglobulin and mucin-domain 3

TNM:

Tumor, node, metastasis

UC:

Urothelial carcinoma of the bladder

References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7

    Article  PubMed  Google Scholar 

  2. Messer JC, Shariat SF, Dinney CP et al (2014) Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis. Urology 83:863

    Article  PubMed  Google Scholar 

  3. Zeegers MP, Tan FE, Dorant E et al (2000) The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer 89:630

    Article  CAS  PubMed  Google Scholar 

  4. Lucca I, Fajkovic H, Klatte T (2014) Sex steroids and gender differences in nonmuscle invasive bladder cancer. Curr Opin Urol 24:500

    Article  PubMed  Google Scholar 

  5. Chamie K, Litwin MS, Bassett JC et al (2013) Recurrence of high-risk bladder cancer: a population-based analysis. Cancer 119:3219

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chan ES, Yip SK, Hou SM et al (2013) Age, tumour stage, and preoperative serum albumin level are independent predictors of mortality after radical cystectomy for treatment of bladder cancer in Hong Kong Chinese. Hong Kong Med J 19:400

    Article  CAS  PubMed  Google Scholar 

  7. Shariat SF, Sfakianos JP, Droller MJ et al (2010) The effect of age and gender on bladder cancer: a critical review of the literature. BJU Int 105:300

    Article  PubMed  Google Scholar 

  8. Paiola M, Knigge T, Duflot A et al (2018) Oestrogen, an evolutionary conserved regulator of T cell differentiation and immune tolerance in jawed vertebrates? Dev Comp Immunol 84:48

    Article  CAS  PubMed  Google Scholar 

  9. Sundahl N, Rottey S, De Maeseneer D et al (2018) Pembrolizumab for the treatment of bladder cancer. Expert Rev Anticancer Ther 18:107

    Article  CAS  PubMed  Google Scholar 

  10. Massari F, Di Nunno V, Cubelli M et al (2018) Immune checkpoint inhibitors for metastatic bladder cancer. Cancer Treat Rev 64:11

    Article  CAS  PubMed  Google Scholar 

  11. Udall M, Rizzo M, Kenny J et al (2018) PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics. Diagn Pathol 13:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Troncone G, Gridelli C (2017) The reproducibility of PD-L1 scoring in lung cancer: can the pathologists do better? Transl Lung Cancer Res 6:S74

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tracey E, Watt H, Currow D et al (2014) Investigation of poorer bladder cancer survival in women in NSW, Australia: a data linkage study. BJU Int 113:437

    Article  PubMed  Google Scholar 

  14. Keller J, Chiou HY, Lin HC (2013) Increased risk of bladder cancer following diagnosis with bladder pain syndrome/interstitial cystitis. Neurourol Urodyn 32:58

    Article  PubMed  Google Scholar 

  15. Takahashi Y, Horio H, Hato T et al (2015) Prognostic significance of preoperative neutrophil-lymphocyte ratios in patients with stage I non-small cell lung cancer after complete resection. Ann Surg Oncol 22(Suppl 3):S1324

    Article  PubMed  Google Scholar 

  16. Proctor MJ, McMillan DC, Morrison DS et al (2012) A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br J Cancer 107:695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Giefing-Kroll C, Berger P, Lepperdinger G et al (2015) How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell 14:309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang L, Du H, Xiao TW et al (2015) Prognostic value of PD-1 and TIM-3 on CD3 + T cells from diffuse large B-cell lymphoma. Biomed Pharmacother 75:83

    Article  CAS  PubMed  Google Scholar 

  19. Xu LY, Chen DD, He JY et al (2014) Tim-3 expression by peripheral natural killer cells and natural killer T cells increases in patients with lung cancer–reduction after surgical resection. Asian Pac J Cancer Prev 15:9945

    Article  PubMed  Google Scholar 

  20. Wu X, Zhang H, Xing Q et al (2014) PD-1(+) CD8(+) T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients. Br J Cancer 111:1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shi F, Shi M, Zeng Z et al (2011) PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 128:887

    Article  CAS  PubMed  Google Scholar 

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Funding

Southern Illinois University School of Medicine research fund.

Author information

Author notes

  1. Bradley C. Holland and Akshay Sood equally contributed.

Authors and Affiliations

  1. Department of Surgery, Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA

    Bradley C. Holland, Kristin Delfino, Danuta I. Dynda & Shaheen Alanee

  2. VCORE-Center for Outcomes Research, Analytics, and Evaluation, Vattikuti Urology Institute, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, MI, 48202, USA

    Akshay Sood & Shaheen Alanee

  3. Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA

    Sophia Ran

  4. Pathology Associates of Central Illinois, Springfield, IL, USA

    Natalie Freed

Authors
  1. Bradley C. Holland
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Contributions

BCH: data collection, manuscript writing. AS: manuscript writing. KD: statistical analysis, manuscript writing. DID: regulatory assistance. SR: immune staining, manuscript writing. NF: immune staining, manuscript writing. SA: study concept, manuscript writing, supervision.

Corresponding author

Correspondence to Shaheen Alanee.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the institutional review board of Southern Illinois University School of Medicine (5/13/2015). No human subjects or animals were involved in the study as it was done on stored tissue.

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Holland, B.C., Sood, A., Delfino, K. et al. Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy. Cancer Immunol Immunother 68, 991–997 (2019). https://doi.org/10.1007/s00262-019-02340-w

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  • DOI: https://doi.org/10.1007/s00262-019-02340-w

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