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CD19+ tumor-infiltrating B-cells prime CD4+ T-cell immunity and predict platinum-based chemotherapy efficacy in muscle-invasive bladder cancer

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Abstract

Purpose

CD19+ tumor-infiltrating B-cells (CD19+ TIB) play a crucial role in tumorigenesis, but their clinical relevance in muscle-invasive bladder cancer (MIBC) remains unknown. This study aimed to investigate the prognostic value of CD19+ TIB for post-surgery survival and adjuvant chemotherapy response in MIBC.

Experimental design

We assessed TIB by immunohistochemical staining of CD19 in 246 MIBC patients from Zhongshan Hospital and Shanghai Cancer Center. We evaluated the survival benefit of platinum-based chemotherapy according to CD19+ TIB. The mechanism underlying CD19+ TIB antitumor immunity was explored through the Cancer Genome Atlas (TCGA) dataset analysis and an in vitro Ag presentation assay.

Results

CD19+ TIB extensively infiltrated into the tumor stroma of MIBC. Adjuvant chemotherapy (ACT) led to a significantly increased benefit in the high CD19+ TIB MIBC patients (P = 0.003). In multivariate analysis, high CD19+ TIB MIBC patients had significantly longer OS with ACT in the discovery set (HR = 0.487, P = 0.038). TCGA gene expression analyses showed enrichment of adaptive immunity, T-cell-mediated immunity, and antigen-presentation signaling pathways in high CD19+ TIB MIBC patients. Moreover, CD19+ TIB co-localized with activated CD4+ TIT and expressed surface markers characteristic of antigen-presenting cells. Finally, an antigen-presentation assay demonstrated the antigen-presentation function of CD19+ TIB.

Conclusion

CD19+ TIB was identified as an independent prognostic factor, which could predict for post-surgery survival and platinum-based ACT benefits in MIBC. CD19+ TIB serve as antigen-presenting cells (APCs) to activate CD4+ TIT in the tumor environment of MIBC.

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Abbreviations

ACT:

Adjuvant chemotherapy

CD19+ TIB:

CD19+ tumor-infiltrating B-cell(s)

GSEA:

Gene set enrichment analysis

MIBC:

Muscle-invasive bladder cancer

RC:

Radical cystectomy

TCGA:

The Cancer Genome Atlas

TIT:

Tumor-infiltrating T-cell(s)

TMA:

Tissue microarray

References

  1. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30. https://doi.org/10.3322/caac.21387

    Article  PubMed  Google Scholar 

  2. Bellmunt J, Orsola A, Leow JJ, Wiegel T, De Santis M, Horwich A, Group EGW (2014) Bladder cancer: ESMO practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 25 Suppl 3: iii40–i8. https://doi.org/10.1093/annonc/mdu223

    Article  PubMed  Google Scholar 

  3. Witjes JA, Comperat E, Cowan NC et al (2014) EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 65:778–792. https://doi.org/10.1016/j.eururo.2013.11.046

    Article  PubMed  Google Scholar 

  4. Alfred Witjes J, Lebret T, Comperat EM et al (2017) Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 71:462–475. https://doi.org/10.1016/j.eururo.2016.06.020

    Article  CAS  PubMed  Google Scholar 

  5. Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M, Koralov SB, Bar-Sagi D (2016) IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov 6:247–255. https://doi.org/10.1158/2159-8290.CD-15-0843

    Article  CAS  PubMed  Google Scholar 

  6. Shalapour S, Lin XJ, Bastian IN et al (2017) Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551:340–345. https://doi.org/10.1038/nature24302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cooper MD (2015) The early history of B cells. Nat Rev Immunol 15:191–197. https://doi.org/10.1038/nri3801

    Article  CAS  PubMed  Google Scholar 

  8. Vidard L, Kovacsovics-Bankowski M, Kraeft SK, Chen LB, Benacerraf B, Rock KL (1996) Analysis of MHC class II presentation of particulate antigens of B lymphocytes. J Immunol 156:2809–2818

    CAS  PubMed  Google Scholar 

  9. Senovilla L, Vacchelli E, Galon J et al (2012) Trial watch: prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 1:1323–1343. https://doi.org/10.4161/onci.22009

    Article  PubMed  PubMed Central  Google Scholar 

  10. Inoue S, Leitner WW, Golding B, Scott D (2006) Inhibitory effects of B cells on antitumor immunity. Cancer Res 66:7741–7747. https://doi.org/10.1158/0008-5472.CAN-05-3766

    Article  CAS  PubMed  Google Scholar 

  11. Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, Mauri C, Coussens LM, Balkwill FR (2011) B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. Proc Natl Acad Sci U S A 108:10662–10667. https://doi.org/10.1073/pnas.1100994108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Montfort A, Pearce O, Maniati E et al (2017) A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin Cancer Res 23:250–262. https://doi.org/10.1158/1078-0432.Ccr-16-0081

    Article  CAS  PubMed  Google Scholar 

  13. Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404. https://doi.org/10.1158/2159-8290.CD-12-0095

    Article  Google Scholar 

  14. Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213. https://doi.org/10.1056/NEJMoa020177

    Article  CAS  Google Scholar 

  15. Ke AW, Shi GM, Zhou J et al (2009) Role of overexpression of CD151 and/or c-met in predicting prognosis of hepatocellular carcinoma. Hepatology 49:491–503. https://doi.org/10.1002/hep.22639

    Article  CAS  PubMed  Google Scholar 

  16. Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12:453–457. https://doi.org/10.1038/nmeth.3337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Murphy K, Weaver C (2016) Janeway’s immunobiology. Garland Science, London. ISBN-13: 978-0-8153-4551-0

    Book  Google Scholar 

  19. Qu Y, Chen L, Lowe DB, Storkus WJ, Taylor JL (2012) Combined Tbet and IL12 gene therapy elicits and recruits superior antitumor immunity in vivo. Mol Ther 20:644–651. https://doi.org/10.1038/mt.2011.283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Davis RE, Ngo VN, Lenz G et al (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88–97. https://doi.org/10.1038/nature08638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22:7265–7279. https://doi.org/10.1038/sj.onc.1206933

    Article  CAS  Google Scholar 

  22. Leow JJ, Martin-Doyle W, Rajagopal PS et al (2014) Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 66:42–54. https://doi.org/10.1016/j.eururo.2013.08.033

    Article  CAS  PubMed  Google Scholar 

  23. Choi W, Porten S, Kim S et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165. https://doi.org/10.1016/j.ccr.2014.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fremd C, Schuetz F, Sohn C, Beckhove P, Domschke C (2013) B cell-regulated immune responses in tumor models and cancer patients. Oncoimmunology 2:e25443. https://doi.org/10.4161/onci.25443

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shi JY, Gao Q, Wang ZC et al (2013) Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin Cancer Res 19:5994–6005. https://doi.org/10.1158/1078-0432.CCR-12-3497

    Article  CAS  PubMed  Google Scholar 

  26. DiLillo DJ, Yanaba K, Tedder TF (2010) B cells are required for optimal CD4 + and CD8 + T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J Immunol 184:4006–4016. https://doi.org/10.4049/jimmunol.0903009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Apetoh L, Ghiringhelli F, Tesniere A et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059. https://doi.org/10.1038/nm1622

    Article  CAS  PubMed  Google Scholar 

  28. Wang W, Kryczek I, Dostal L et al (2016) Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165:1092–1105. https://doi.org/10.1016/j.cell.2016.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by grants from the National Natural Science Foundation of China (81471621, 81472227, 81671628, 31770851, 81871306 and 81872082), the Shanghai Municipal Natural Science Foundation (17ZR1405100), the Shanghai Sailing Program (18YF1404500) and the Shanghai Municipal Commission of Health and Family Planning Program (20144Y0223). The study sponsors had no roles in the study design or in the collection, analysis, and interpretation of data.

Author information

Author notes

  1. Qi Jiang, Qiang Fu and Yuan Chang contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Fudan University, Building 13, No. 130, Dongan Road, Shanghai, 200032, China

    Qi Jiang & Weijuan Zhang

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Building 7, No. 130, Dongan Road, Shanghai, 200032, China

    Qiang Fu & Jiejie Xu

  3. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Yuan Chang, Zheng Liu, Junyu Zhang & Yu Zhu

  4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Yuan Chang, Zheng Liu, Junyu Zhang & Yu Zhu

  5. Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Le Xu

  6. Department of Urology, Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Yiwei Wang

Authors
  1. Qi Jiang
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  2. Qiang Fu
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  3. Yuan Chang
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  4. Zheng Liu
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Contributions

QJ, QF and YC: acquisition of data, analysis and interpretation of data, statistical analysis and drafting the manuscript. ZL, JZ, LX, YZ and YW: technical and material support. WZ and JX: study concept and design, analysis and interpretation of data, drafting the manuscript, obtained the funding and study supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Weijuan Zhang or Jiejie Xu.

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Conflict of interest

The authors declare no conflict of interest.

Ethical approval and ethical standards

This study was approved by the institutional ethical review boards of Zhongshan Hospital, Fudan University (Registration no. B2015-030) and Fudan University Shanghai Cancer Center (Registration no. 050432-4-1212B). Written informed consent approved by the institutional ethics committee was obtained from each patient.

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Jiang, Q., Fu, Q., Chang, Y. et al. CD19+ tumor-infiltrating B-cells prime CD4+ T-cell immunity and predict platinum-based chemotherapy efficacy in muscle-invasive bladder cancer. Cancer Immunol Immunother 68, 45–56 (2019). https://doi.org/10.1007/s00262-018-2250-9

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  • DOI: https://doi.org/10.1007/s00262-018-2250-9

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