Skip to main content

Advertisement

SpringerLink
Log in

Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The expression status of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and the infiltration of CD8+ T cells in tumor tissues are considered to be related to immunotherapy efficacy and patient prognosis. The purpose of this study is to clarify the prognostic value of the PD-L1/PD-1/CD8 axis, and to develop and validate a comprehensive scoring system based on multiple immune variables to predict cancer survival of upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). The immunohistochemical method was used to detect the expression of PD-L1, PD-1, and CD8 in cancer tissues of UTUC patients after RNU. Then, an immunoscore was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model in the training cohort (n = 120), and it was verified in the validation cohort (n = 54). We found that infiltration of PD-L1+ immune cells (ICs), stromal PD-1+ tumor-infiltrating lymphocytes (TILs), and intratumoral CD8+ TILs was associated with poor overall survival (OS). The immunoscore based on the three immune variables further divided the patients into low- and high-risk groups, and there was a significant difference in the survival rate. A nomogram was constructed by combining tumor-node-metastasis (TNM) stage and immunoscore, and the area under the curve of the receiver-operating characteristic (ROC) (0.78) for predicting 5-year mortality was better than that of the TNM stage (0.70) and immunoscore (0.76). Our results show that the PD-L1/PD-1/CD8 axis-based classifier have potential clinical application to predict cancer survival of UTUC patients after RNU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Rouprêt M, Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Cowan NC, Dominguez-Escrig JL, Gontero P, Hugh Mostafid A, Palou J, Peyronnet B, Seisen T, Soukup V, Sylvester RJ, Rhijn B, Zigeuner R, Shariat SF (2020) European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 update. Eur Urol. https://doi.org/10.1016/j.eururo.2020.05.042

    Article  PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551

    Article  PubMed  Google Scholar 

  3. Margulis V, Shariat SF, Matin SF, Kamat AM, Zigeuner R, Kikuchi E, Lotan Y, Weizer A, Raman JD, Wood CG (2009) Outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. Cancer 115(6):1224–1233. https://doi.org/10.1002/cncr.24135

    Article  PubMed  Google Scholar 

  4. Lughezzani G, Burger M, Margulis V, Matin SF, Novara G, Roupret M, Shariat SF, Wood CG, Zigeuner R (2012) Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature. Eur Urol 62(1):100–114. https://doi.org/10.1016/j.eururo.2012.02.030

    Article  PubMed  Google Scholar 

  5. Seisen T, Peyronnet B, Dominguez-Escrig JL, Bruins HM, Yuan CY, Babjuk M, Böhle A, Burger M, Compérat EM, Cowan NC, Kaasinen E, Palou J, van Rhijn BW, Sylvester RJ, Zigeuner R, Shariat SF, Rouprêt M (2016) Oncologic outcomes of kidney-sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma: a systematic review by the EAU non-muscle invasive bladder cancer guidelines panel. Eur Urol 70(6):1052–1068. https://doi.org/10.1016/j.eururo.2016.07.014

    Article  PubMed  Google Scholar 

  6. Leow JJ, Martin-Doyle W, Fay AP, Choueiri TK, Chang SL, Bellmunt J (2014) A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol 66(3):529–541. https://doi.org/10.1016/j.eururo.2014.03.003

    Article  PubMed  Google Scholar 

  7. Seisen T, Krasnow RE, Bellmunt J, Rouprêt M, Leow JJ, Lipsitz SR, Vetterlein MW, Preston MA, Hanna N, Kibel AS, Sun M, Choueiri TK, Trinh QD, Chang SL (2017) Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma. J Clin Oncol 35(8):852–860. https://doi.org/10.1200/jco.2016.69.4141

    Article  PubMed  Google Scholar 

  8. Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schöffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB (2018) Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19(1):51–64. https://doi.org/10.1016/s1470-2045(17)30900-2

    Article  CAS  PubMed  Google Scholar 

  9. Fang D, Zhang Q, Li X, Qian C, Xiong G, Zhang L, Chen X, Zhang X, Yu W, He Z, Zhou L (2014) Nomogram predicting renal insufficiency after nephroureterectomy for upper tract urothelial carcinoma in the Chinese population: exclusion of ineligible candidates for adjuvant chemotherapy. Biomed Res Int 2014:529186. https://doi.org/10.1155/2014/529186

    Article  PubMed  PubMed Central  Google Scholar 

  10. Xiong G, Chen X, Li X, Fang D, Zhang L, Yang L, Zhang L, Yao L, He Z, Zhou L (2014) Prevalence and factors associated with baseline chronic kidney disease in China: a 10-year study of 785 upper urinary tract urothelial carcinoma patients. Journal of the Formosan Medical Association = Taiwan yi zhi 113(8):521–526. https://doi.org/10.1016/j.jfma.2013.04.001

    Article  PubMed  Google Scholar 

  11. EAU Guidelines. Edn. Presented at the EAU Annual Congress Barcelona 2019. ISBN 978-94-92671-04-2

  12. Yang HY, Yang CC, Wu CY, Wang LJ, Lu KL (2019) Aristolochic acid and immunotherapy for urothelial carcinoma: directions for unmet needs. Int J Mol Sci. https://doi.org/10.3390/ijms20133162

    Article  PubMed  PubMed Central  Google Scholar 

  13. Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell Infiltration and PD-L1. Cancer Res 75(11):2139–2145. https://doi.org/10.1158/0008-5472.Can-15-0255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhu J, Armstrong AJ, Friedlander TW, Kim W, Pal SK, George DJ, Zhang T (2018) Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond. J Immunotherapy Cancer 6(1):4. https://doi.org/10.1186/s40425-018-0314-1

    Article  Google Scholar 

  15. Wang B, Pan W, Yang M, Yang W, He W, Chen X, Bi J, Jiang N, Huang J, Lin T (2019) Programmed death ligand-1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder. Cancer Sci 110(2):489–498. https://doi.org/10.1111/cas.13887

    Article  CAS  PubMed  Google Scholar 

  16. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, Bajorin DF, Reuter VE, Herr H, Old LJ, Sato E (2007) CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA 104(10):3967–3972. https://doi.org/10.1073/pnas.0611618104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Skala SL, Liu TY, Udager AM, Weizer AZ, Montgomery JS, Palapattu GS, Siddiqui J, Cao X, Fields K, Abugharib AE, Soliman M, Hafez KS, Miller D, Lee CT, Alva A, Chinnaiyan AM, Morgan TM, Spratt DE, Jiang H, Mehra R (2017) Programmed death-ligand 1 expression in upper tract urothelial carcinoma. Eur Urol Focus 3(4–5):502–509. https://doi.org/10.1016/j.euf.2016.11.011

    Article  PubMed  Google Scholar 

  18. Krabbe LM, Heitplatz B, Preuss S, Hutchinson RC, Woldu SL, Singla N, Boegemann M, Wood CG, Karam JA, Weizer AZ, Raman JD, Remzi M, Rioux-Leclercq N, Haitel A, Rapoport LM, Glybochko PV, Roscigno M, Bolenz C, Bensalah K, Sagalowsky AI, Shariat SF, Lotan Y, Xylinas E, Margulis V (2017) Prognostic Value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma. J Urol 198(6):1253–1262. https://doi.org/10.1016/j.juro.2017.06.086

    Article  CAS  PubMed  Google Scholar 

  19. Miyama Y, Morikawa T, Miyakawa J, Koyama Y, Kawai T, Kume H, Fukayama M (2018) The prognostic value of PD-L1 expression in upper tract urothelial carcinoma varies according to platelet count. Cancer Med 7(9):4330–4338. https://doi.org/10.1002/cam4.1686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19(3):133–150. https://doi.org/10.1038/s41568-019-0116-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, Overberg P, Rose I, Basu GD, Vranic S, Lynch HT, Von Hoff DD, Hamid O (2014) Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomark Prev 23(12):2965–2970. https://doi.org/10.1158/1055-9965.Epi-14-0654

    Article  CAS  Google Scholar 

  22. Cha JH, Chan LC, Li CW, Hsu JL, Hung MC (2019) Mechanisms controlling PD-L1 expression in cancer. Mol Cell 76(3):359–370. https://doi.org/10.1016/j.molcel.2019.09.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kubota K, Moriyama M, Furukawa S, Rafiul H, Maruse Y, Jinno T, Tanaka A, Ohta M, Ishiguro N, Yamauchi M, Sakamoto M, Maehara T, Hayashida JN, Kawano S, Kiyoshima T, Nakamura S (2017) CD163 (+)CD204 (+) tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma. Sci Rep 7(1):1755. https://doi.org/10.1038/s41598-017-01661-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England) 387(10031):1909–1920. https://doi.org/10.1016/s0140-6736(16)00561-4

    Article  CAS  Google Scholar 

  25. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543. https://doi.org/10.1073/pnas.0509182102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, Aoe K, Gemba K, Kishimoto T, Torigoe T, Nishimura M (2010) CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunotherapy CII 59(10):1543–1549. https://doi.org/10.1007/s00262-010-0881-6

    Article  CAS  PubMed  Google Scholar 

  27. Ye SL, Li XY, Zhao K, Feng T (2017) High expression of CD8 predicts favorable prognosis in patients with lung adenocarcinoma: a cohort study. Medicine 96(15):e6472. https://doi.org/10.1097/md.0000000000006472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hsu MC, Hsiao JR, Chang KC, Wu YH, Su IJ, Jin YT, Chang Y (2010) Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma. Modern Pathol 23(10):1393–1403. https://doi.org/10.1038/modpathol.2010.130

    Article  CAS  Google Scholar 

  29. Wen T, Wang Z, Li Y, Li Z, Che X, Fan Y, Wang S, Qu J, Yang X, Hou K, Zhou W, Xu L, Li C, Wang J, Liu J, Chen L, Zhang J, Qu X, Liu Y (2017) A Four-factor immunoscore system that predicts clinical outcome for stage II/III gastric cancer. Cancer Immunol Res 5(7):524–534. https://doi.org/10.1158/2326-6066.Cir-16-0381

    Article  CAS  PubMed  Google Scholar 

  30. Hou W, Xue M, Shi J, Yang M, Zhong W, Fan X, Zeng H, Lai Y, Huang J, Wang B, Lin T (2020) PD-1 topographically defines distinct T cell subpopulations in urothelial cell carcinoma of the bladder and predicts patient survival. Urol Oncol 38(8):685.e681-685.e610. https://doi.org/10.1016/j.urolonc.2020.04.009

    Article  CAS  Google Scholar 

  31. van Dijk N, Funt SA, Blank CU, Powles T, Rosenberg JE, van der Heijden MS (2019) The Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer. Eur Urol 75(3):435–444. https://doi.org/10.1016/j.eururo.2018.09.022

    Article  CAS  PubMed  Google Scholar 

  32. Shukuya T, Carbone DP (2016) Predictive Markers for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Lung Cancer. J Thoracic Oncol 11(7):976–988. https://doi.org/10.1016/j.jtho.2016.02.015

    Article  Google Scholar 

  33. Mitra D, Horick NK, Brackett DG, Mouw KW, Hornick JL, Ferrone S, Hong TS, Mamon H, Clark JW, Parikh AR, Allen JN, Ryan DP, Ting DT, Deshpande V, Wo JY (2019) High IDO1 expression is associated with poor outcome in patients with anal cancer treated with definitive chemoradiotherapy. Oncologist 24(6):e275–e283. https://doi.org/10.1634/theoncologist.2018-0794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhou L, Li Y, Gao W, Huangfu H, Wen S, Zhang C, Zhao Q, Dong Z, Qu C, Li G, Wu L, Wang B (2019) Assessment of tumor-associated immune cells in laryngeal squamous cell carcinoma. J Cancer Res Clin Oncol 145(7):1761–1772. https://doi.org/10.1007/s00432-019-02936-w

    Article  CAS  PubMed  Google Scholar 

  35. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. https://doi.org/10.1038/nature14011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (Grant nos. 81772719, 81825016, 81902586, 81961128027); Guangdong Basic and Applied Basic Research Foundation (2020A1515011312); China Postdoctoral Science Foundation (2018M640862, 2019M653196); Fundamental Research Funds for the Central Universities (19ykpy116, 19ykpy117); Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun-Yat-Sen University (Grant no. KLB09001); Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology (Grant no. 013-163).

Author information

Author notes

  1. Junyu Chen, Wenlong Zhong and Meng Yang have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhongshan) University, Guangzhou, 510120, People’s Republic of China

    Junyu Chen, Wenlong Zhong, Weibin Hou, Xiaofei Wang, Kun Xia, Hao Yu, Meihua Yang, Bingkun Zhou, Bo Wang, Jian Huang & Tianxin Lin

  2. Kashgar Prefecture First People’s Hospital of Kashi, Xinjiang, People’s Republic of China

    Tianxin Lin

  3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Junyu Chen, Wenlong Zhong, Weibin Hou, Xiaofei Wang, Kun Xia, Hao Yu, Meihua Yang, Bingkun Zhou, Bo Wang, Jian Huang & Tianxin Lin

  4. Department of Urology, Yan’ an Hospital of Kunming City, Kunming Medical University, Kunming, People’s Republic of China

    Meng Yang

Authors
  1. Junyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenlong Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weibin Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaofei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kun Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Meihua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bingkun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tianxin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JYC and WLZ designed the study and wrote the manuscript; MY and KX collected and analyzed the clinical data and pathological review; WBH and XFW performed immunohistochemistry and immunofluorescence staining; HY, MHY, BKZ, and BW modified and revised the manuscript; JH and TXL performed the surgeries and made important revisions to the manuscript. All authors have approved the submission of this manuscript.

Corresponding authors

Correspondence to Bo Wang, Jian Huang or Tianxin Lin.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 504 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Zhong, W., Yang, M. et al. Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy. Cancer Immunol Immunother 70, 2657–2668 (2021). https://doi.org/10.1007/s00262-020-02827-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-020-02827-x

Keywords

Search

Navigation