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Prognostic Role of the Immunoscore for Patients with Urothelial Carcinoma of the Bladder Who Underwent Radical Cystectomy

  • Urologic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

A Correction to this article was published on 22 November 2019

This article has been updated

Abstract

Background

Increasing evidence suggests that cancer progression is strongly influenced by the host immune response, which is represented by immune cell infiltrates. The T-lymphocyte-based Immunoscore is reported to be a reliable prognostic factor in colon cancer, but its significance in urothelial carcinoma of the bladder (UCB) is at an early stage of exploration. This study aimed to determine whether the tumor immune infiltrate, as evaluated by the Immunoscore, could act as a useful prognostic marker for UCB patients who have undergone radical cystectomy (RC).

Methods

In this study, immunohistochemistry was used to examine the Immunoscore of 221 UCB patients who underwent RC. The Immunoscore of the patients was determined by the densities of CD3+ and CD8+ T cells at the tumor center and the invasive margin.

Results

A highly significant association between a low Immunoscore and a shortened patient survival (P < 0.001, log-rank test) was demonstrated. In different subsets of UCB patients, a low Immunoscore also was a prognostic indicator of pT ≤ 2, pN(–)-status tumors, negative vascular invasion, or both (P < 0.05). Importantly, the Immunoscore together with the patient’s pT status provided significant independent prognostic parameters in the multivariate analysis (P < 0.05). Furthermore, a significant correlation (P = 0.003) of a low Immunoscore with an increased UCB labeling index of Ki-67 (a cell proliferation marker) was observed in this UCB cohort.

Conclusions

The findings suggest that the Immunoscore, as examined by immunohistochemistry, might serve as a novel prognostic marker for UCB patients who have undergone RC.

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Availability of Data and Materials

The key raw data have been deposited into the Research Data Deposit (http://www.researchdata.org.cn), with the approval number of RDDB2019000530.

Change history

  • 22 November 2019

    In the original article, the word IMMUNOSCORE<Superscript>®</Superscript> was not displayed to reflect its trademark status. At every mention, IMMUNOSCORE<Superscript>®</Superscript> should be in all caps and with a registered trademark symbol.

References

  1. Jacobs BL, Lee CT, Montie JE. Bladder cancer in 2010: how far have we come? CA: Cancer J Clin. 2010;60:244–72.

    Google Scholar 

  2. Abdollah F, Sun M, Schmitges J, et al. Stage-specific impact of pelvic lymph node dissection on survival in patients with non-metastatic bladder cancer treated with radical cystectomy. BJU Int. 2012;109:1147–54.

    Article  Google Scholar 

  3. Witjes JA, Comperat E, Cowan NC, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014;65:778–92.

    Article  Google Scholar 

  4. Sternberg CN, Bellmunt J, Sonpavde G, et al. ICUD-EAU international consultation on bladder cancer 2012: chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. Eur Urol. 2013;63:58–66.

    Article  Google Scholar 

  5. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol. 2001;19:666–75.

    Article  CAS  Google Scholar 

  6. Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol. 2004;22:2781–9.

    Article  Google Scholar 

  7. Brierley JD, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumors. UICC International Union Against Cancer. 8th ed. Chichester, UK: Wiley-Blackwell; 2017.

    Google Scholar 

  8. Prasad SM, Decastro GJ, Steinberg GD. Urothelial carcinoma of the bladder: definition, treatment, and future efforts. Nat Rev Urol. 2011;8:631–42.

    Article  CAS  Google Scholar 

  9. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer: a current perspective. Nat Rev Urol. 2014;11:153–62.

    Article  CAS  Google Scholar 

  10. Slovin SF. Biomarkers for immunotherapy in genitourinary malignancies. Urol Oncol. 2016;34:205–13.

    Article  CAS  Google Scholar 

  11. Krpina K, Babarovic E, Dordevic G, Fuckar Z, Jonjic N. The association between the recurrence of solitary non-muscle invasive bladder cancer and tumor-infiltrating lymphocytes. Croat Med J. 2012;53:598–604.

    Article  CAS  Google Scholar 

  12. Baras AS, Drake C, Liu JJ, et al. The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. Oncoimmunology. 2016;5:e1134412.

    Article  Google Scholar 

  13. Sjodahl G, Lovgren K, Lauss M, et al. Infiltration of CD3(+) and CD68(+) cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol Oncol. 2014;32:791–7.

    Article  Google Scholar 

  14. Galon J, Mlecnik B, Bindea G, et al. Towards the introduction of the “Immunoscore” in the classification of malignant tumours. J Pathol. 2014;232:199–209.

    Article  CAS  Google Scholar 

  15. Mlecnik B, Van den Eynde M, Bindea G, et al. Comprehensive intrametastatic immune quantification and major impact of Immunoscore on survival. J Natl Cancer Inst. 2018;110:97–108.

    Article  CAS  Google Scholar 

  16. Jiang Y, Zhang Q, Hu Y, et al. ImmunoScore Signature: a prognostic and predictive tool in gastric cancer. Ann Surg. 2018;267:504–13.

    Article  Google Scholar 

  17. Anitei MG, Zeitoun G, Mlecnik B, et al. Prognostic and predictive values of the immunoscore in patients with rectal cancer. Clin Cancer Res. 2014;20:1891–9.

    Article  Google Scholar 

  18. Tahkola K, Mecklin JP, Wirta EV, et al. High immune cell score predicts improved survival in pancreatic cancer. Virchows Arch. 2018;472:653–65.

    Article  CAS  Google Scholar 

  19. Pages F, Mlecnik B, Marliot F, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet Lond Engl. 2018;391:2128–39.

    Article  Google Scholar 

  20. Ingels A, Sanchez Salas RE, Ravery V, et al. T-helper 1 immunoreaction influences survival in muscle-invasive bladder cancer: proof of concept. Ecancermedicalscience. 2014;8:486.

    Article  Google Scholar 

  21. Yu A, Mansure JJ, Solanki S, et al. Presence of lymphocytic infiltrate cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy. PloS ONE. 2018;13:e0205746.

    Article  Google Scholar 

  22. Marisa L, Svrcek M, Collura A, et al. The balance between cytotoxic t-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors. J Natl Cancer Inst. 2018;110:68–77.

    Article  CAS  Google Scholar 

  23. Mlecnik B, Bindea G, Kirilovsky A, et al. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med. 2016;8: 327ra326.

    Article  Google Scholar 

  24. Gabrielson A, Wu Y, Wang H, et al. Intratumoral CD3 and CD8 T cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016;4:419–30.

    Article  CAS  Google Scholar 

  25. Vayrynen JP, Vornanen JO, Sajanti S, Bohm JP, Tuomisto A, Makinen MJ. An improved image analysis method for cell counting lends credibility to the prognostic significance of T cells in colorectal cancer. Virchows Arch. 2012;460:455–65.

    Article  Google Scholar 

  26. Yoon HH, Shi Q, Heying EN, et al. Intertumoral heterogeneity of CD3(+) and CD8(+) T cell densities in the microenvironment of DNA mismatch-repair-deficient colon cancers: implications for prognosis. Clin Cancer Res. 2019;25:125–33.

    Article  Google Scholar 

  27. Li XD, Chen SL, Dong P, et al. Overexpression of RNF2 is an independent predictor of outcome in patients with urothelial carcinoma of the bladder undergoing radical cystectomy. Sci Rep. 2016;6:20894.

    Article  CAS  Google Scholar 

  28. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  Google Scholar 

  29. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16:76–86.

    Article  Google Scholar 

  30. Streeper NM, Simons CM, Konety BR, et al. The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer. BJU Int. 2009;103:475–9.

    Article  Google Scholar 

  31. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  CAS  Google Scholar 

  32. Spranger S, Gajewski TF. A new paradigm for tumor immune escape: beta-catenin-driven immune exclusion. J Immunother Cancer. 2015;3:43.

    Article  Google Scholar 

  33. Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013;19:393–403.

    Article  CAS  Google Scholar 

  34. Lanaya H, Natarajan A, Komposch K, et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 2014;16:972–7.

    Article  CAS  Google Scholar 

  35. Angelova M, Mlecnik B, Vasaturo A, et al. Evolution of metastases in space and time under immune selection. Cell. 2018;175:751–65.e716.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by funds from the Nature Science Foundation of China (Nos. 81772716 and 81472385) and the Science and Technology Planning Project of Guangdong Province (No. 2017B020227007).

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Author notes

  1. The authors Xiang-Dong Li, Chao-Wen Huang and Ze-Fu Liu have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    Xiang-Dong Li MD, Chao-Wen Huang MD, Ze-Fu Liu MD, Li-Juan Jiang MD, Jie-Wei Chen MD, Dan Xie MD, PhD, Fang-Jian Zhou MD, PhD, Hui-Ming Lu MD & Zhuo-Wei Liu MD, PhD

  2. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Xiang-Dong Li MD, Chao-Wen Huang MD, Ze-Fu Liu MD, Li-Juan Jiang MD, Fang-Jian Zhou MD, PhD, Hui-Ming Lu MD & Zhuo-Wei Liu MD, PhD

  3. Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Jie-Wei Chen MD & Dan Xie MD, PhD

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Contributions

HML, ZWL and XDL designed the research and wrote the paper. XDL, CWH, ZFL, LJJ, HML and FJZ analyzed data and prepared figures. CWH, LJJ, JWC and DX advised on the research design and collected the clinical information. ZWL finalized the paper for submission. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hui-Ming Lu MD or Zhuo-Wei Liu MD, PhD.

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Li, XD., Huang, CW., Liu, ZF. et al. Prognostic Role of the Immunoscore for Patients with Urothelial Carcinoma of the Bladder Who Underwent Radical Cystectomy. Ann Surg Oncol 26, 4148–4156 (2019). https://doi.org/10.1245/s10434-019-07529-y

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