Skip to main content

Advertisement

SpringerLink
Log in

Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Programmed cell death ligand 1 (PD-L1) regulates immune responses through interaction with its receptor. PD-L1 is not only a predictor of poor prognosis but also a new therapeutic target in several malignancies. Neoadjuvant chemoradiotherapy (CRT) is an effective tool for local control of rectal cancer, but the disease recurrence rate remains high. The aim of this study was to retrospectively evaluate the correlation between PD-L1 expression and clinicopathological variables in rectal cancer after neoadjuvant CRT.

Materials and methods

A total of 90 rectal cancer patients who underwent neoadjuvant CRT were enrolled in this study. We evaluated PD-L1 expression using immunohistochemistry. Moreover, we investigated the correlation between PD-L1 expression and tumor-infiltrating T cells, and between CD8- and Foxp3-positive cells.

Results

Patients with high PD-L1 expression more frequently had vascular invasion and tumor recurrence compared to patients with low PD-L1 expression (P = 0.0225 and P = 0.0051). High PD-L1 expression was significantly associated with poor recurrence-free and overall survival (P = 0.0027 and P = 0.0357). Multivariate analysis revealed lymph node metastasis and high PD-L1 expression as independent risk factors for tumor recurrence (P = 0.0102 and P = 0.0374). Numbers of infiltrating CD8-positive cells in patients with high PD-L1 expression were significantly lower than in patients with low PD-L1 expression (P = 0.0322).

Conclusion

Our data suggest that inhibition of PD-L1 may be a new immunotherapeutic strategy to reduce tumor recurrence and improve prognosis in patients with rectal cancer after neoadjuvant CRT.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

    Article  CAS  PubMed  Google Scholar 

  2. van den Brink M, Stiggelbout AM, van den Hout WB et al (2004) Clinical nature and prognosis of locally recurrent rectal cancer after total mesorectal excision with or without preoperative radiotherapy. J Clin Oncol 22:3958–3964

    Article  PubMed  Google Scholar 

  3. Guillem JG, Chessin DB, Cohen AM et al (2005) Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241:829–836 discussion 836–828

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123

    Article  CAS  PubMed  Google Scholar 

  5. Peeters KC, Marijnen CA, Nagtegaal ID et al (2007) The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693–701

    Article  PubMed  Google Scholar 

  6. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A (2014) Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol 153:145–152

    Article  CAS  PubMed  Google Scholar 

  7. Dolan DE, Gupta S (2014) PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control 21:231–237

    PubMed  Google Scholar 

  8. Francisco LM, Sage PT, Sharpe AH (2010) The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 236:219–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Keir ME, Liang SC, Guleria I et al (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203:883–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704

    Article  CAS  PubMed  Google Scholar 

  11. Dong H, Strome SE, Salomao DR et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800

    Article  CAS  PubMed  Google Scholar 

  12. Sabatier R, Finetti P, Mamessier E et al (2015) Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6:5449–5464

    Article  PubMed  Google Scholar 

  13. Shen JK, Cote GM, Choy E et al (2014) Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res 2:690–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Curiel TJ, Wei S, Dong H et al (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567

    Article  CAS  PubMed  Google Scholar 

  15. Zhang L, Gajewski TF, Kline J (2009) PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 114:1545–1552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iwai Y, Ishida M, Tanaka Y et al (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99:12293–12297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hirano F, Kaneko K, Tamura H et al (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:1089–1096

    CAS  PubMed  Google Scholar 

  18. Yang W, Chen PW, Li H, Alizadeh H, Niederkorn JY (2008) PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci 49:2518–2525

    Article  PubMed  PubMed Central  Google Scholar 

  19. Saigusa S, Inoue Y, Tanaka K et al (2013) Lack of M30 expression correlates with factors reflecting tumor progression in rectal cancer with preoperative chemoradiotherapy. Mol Clin Oncol 2:99–104

    PubMed  PubMed Central  Google Scholar 

  20. Ryan R, Gibbons D, Hyland JM et al (2005) Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 47:141–146

    Article  CAS  PubMed  Google Scholar 

  21. Pages F, Berger A, Camus M et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666

    Article  CAS  PubMed  Google Scholar 

  22. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  CAS  PubMed  Google Scholar 

  23. Mori K, Toiyama Y, Saigusa S et al (2015) Systemic analysis of predictive biomarkers for recurrence in colorectal cancer patients treated with curative surgery. Dig Dis Sci 60:2477–2487

    Article  CAS  PubMed  Google Scholar 

  24. Amarnath S, Mangus CW, Wang JC et al (2011) The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med 3:111ra120

    Article  PubMed  PubMed Central  Google Scholar 

  25. Salama P, Phillips M, Grieu F et al (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192

    Article  PubMed  Google Scholar 

  26. Yoon HH, Orrock JM, Foster NR et al (2012) Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon carcinomas. PLoS One 7:e42274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang Y, Liao H, Zhang Y et al (2014) Prognostic value of tumor-infiltrating FoxP3+ T cells in gastrointestinal cancers: a meta analysis. PLoS One 9:e94376

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shinto E, Hase K, Hashiguchi Y et al (2014) CD8+ and FOXP3+ tumor-infiltrating T cells before and after chemoradiotherapy for rectal cancer. Ann Surg Oncol 21(Suppl 3):S414–S421

    Article  PubMed  Google Scholar 

  29. Tsuchikawa T, Md MM, Yamamura Y et al (2012) The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma. Ann Surg Oncol 19:1713–1719

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Susumu Saigusa, Yuji Toiyama, Koji Tanaka, Yasuhiro Inoue, Koichiro Mori, Shozo Ide, Hiroki Imaoka, Mikio Kawamura, Yasuhiko Mohri & Masato Kusunoki

Authors
  1. Susumu Saigusa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuji Toiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koji Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhiro Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koichiro Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shozo Ide
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroki Imaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mikio Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasuhiko Mohri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masato Kusunoki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susumu Saigusa.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saigusa, S., Toiyama, Y., Tanaka, K. et al. Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol 21, 946–952 (2016). https://doi.org/10.1007/s10147-016-0962-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-016-0962-4

Keywords

Search

Navigation