Role of PD-1/PD-L1-mediated tumour immune escape mechanism and microsatellite instability in the BCG failure of high-grade urothelial carcinomas


Salman F. G., Kankaya D., ÖZAKINCI H., Şahin Y., Kubilay E., SÜER E., ...More

Turkish Journal of Medical Sciences, vol.52, no.6, pp.1802-1813, 2022 (SCI-Expanded) identifier identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 52 Issue: 6
  • Publication Date: 2022
  • Doi Number: 10.55730/1300-0144.5526
  • Journal Name: Turkish Journal of Medical Sciences
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, EMBASE, MEDLINE, Veterinary Science Database, TR DİZİN (ULAKBİM)
  • Page Numbers: pp.1802-1813
  • Keywords: Nonmuscle-invasive bladder carcinoma, microsatellite instability, mismatch repair, PD-L1, immunotherapy, BCG therapy
  • Hacettepe University Affiliated: No

Abstract

© TÜBİTAK.Background/aim: Intravesical BCG treatment fails inexplicably in 30%–45% of patients for high-grade nonmuscle-invasive bladder cancer (NMIBC). We aimed to investigate the role of PD-1/PD-L1 interaction on BCG failure of high-grade NMIBC and to identify biomarkers for predicting BCG responsive cases. Materials and methods: Thirty BCG responsive and 29 nonresponsive NMIBCs were included in the study. Expressions of PD-L1(SP-263), MSH2, MSH6, PMS2, and MLH1 were evaluated on pre-and post-BCG transurethral resection (TUR-B) specimens by immunohistochemistry. PD-L1(SP-263) expression was categorised as negative/low, high. DNA mismatch repair protein (MMR) expressions were classified as “reduced” if ≤30% of nuclei stained, “preserved” if >30% of nuclei stained. Microsatellite instability (MSI) testing was performed by PCR using five mononucleotide markers. Results: Reduced DNA MMR protein expression was found to be significantly higher in the pretreatment biopsies of BCG-responsive group than the BCG nonresponsive tumour group (p = 0.022). PD-L1 expression did not show any significant difference between the pre-and posttreatment TUR-B specimens of the BCG nonresponsive tumour group or between the pretreatment TUR-B specimens of BCG nonresponsive and the BCG responsive groups (p = 0.508, p = 0.708, respectively). Conclusion: Immune escape of tumour cells by PD-1/PD-L1 interaction does not seem to have any role in BCG failure of NMIBCs. Reduced MMR expression may help to determine cases that will respond well to BCG therapy. A better antitumour activity of BCG in NMIBCs with reduced MMR expression may be related to the ongoing accumulation of cancer neoantigens in correlation with increased tumour mutation load as a result of DNA repair defects.