Expression of tumoral GSK3-β, PD-L1, and CD8 cell density in urothelial carcinomas, association with tumor grade and overall survival

Aline Kimberly Almeida Rodrigues; Paulo Goberlanio Silva; Cleto Nogueira; Samuel S Ferreira; Juliana Cordeiro; Benedito Carneiro; Fabio Tavora

Expression of tumoral GSK3-β, PD-L1, and CD8 cell density in urothelial carcinomas, association with tumor grade and overall survival

Am J Clin Exp Immunol. 2023 Oct 15;12(5):87-97. eCollection 2023.

Authors

Aline Kimberly Almeida Rodrigues¹, Paulo Goberlanio Silva¹, Cleto Nogueira^{2

3}, Samuel S Ferreira^{2

3}, Juliana Cordeiro^{2

3}, Benedito Carneiro⁴, Fabio Tavora^{2

3}

Affiliations

¹ ICC (Ceara Cancer Institute), Laboratory of Molecular Biology and Genetics Fortaleza, CE, Brazil.
² Argos Laboratory Fortaleza, CE, Brazil.
³ Department of Pathology and Legal Medicine, Federal University of Ceara Fortaleza, CE, Brazil.
⁴ Department of Oncology, Brown University Providence, RI, USA.

PMID: 38022872
PMCID: PMC10658161

Abstract

Bladder cancer is the most common malignancy in the urinary tract, and is biologically and clinically quite heterogeneous. Around 90% of diagnoses are made in the 6^th decade, being more prevalent in males. The programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) axis play a putative role in immune checkpoint and as a means through which cancer evades the immune system. Inhibition of the glicogênio synthase kinase (GSK) 3 leads to the downregulation of PD-1 via upregulation of the transcription factor Tbet. The use of biomarkers PD-L1 and GSK-3β and evaluation of the immune infiltrate have very promising correlations with urothelial carcinoma prognosis and treatment prediction.

Objective: To investigate the protein expression of PD-L1 and GSK-3β and the CD8-positive immune infiltrates in bladder carcinomas.

Materials and methods: This was a cross-sectional study of 140 samples of urothelial carcinomas from 2015 to 2018. Automated digitally assisted scoring and conventional analyses of the markers of GSK-3β (27C10), CD8 (7103β) and PDL-1 (22c3), were reviewed by two pathologists independently and a histologic score was calculated. The density of CD8 was also measured.

Results: The immunoexpression of GSK-3β (91%) was presented in most samples, PD-L1 in 62.9% and CD8 cells present in 46.3% of cases. When analyzed in conjunction, the levels of GSK-3β and PD-L1 (P = 0.033), and CD8 and PD-L1 (P<0.002) showed significant correlations. No significant associations were observed between GSK-3β and CD8. The positivity of GSK-3β and PD-L1 was predominant in high-grade tumors.

Conclusion: Despite the tumor microenvironment heterogeneity, the expression of CD8, GSK-3β and PDL1 could be valuable and GSK-3β could be a potential target in advanced bladder cancer, especially in the context of immunotherapy.

Keywords: Bladder cancer; CD8; glicogênio synthase kinase (GSK) 3; immunohistochemistry; immunotherapy; programmed cell death ligand 1 (PD-L1); urothelial carcinoma.