Immunoexpression of PD-L1 and PD-1 and Its Clinicopathological Correlation in Urothelial Carcinomas

Abstract

Introduction Urothelial carcinomas are the most common types of bladder tumors that have recently shown a changing trend in treatment protocols with the introduction and approval of immune checkpoint inhibitors. The most important immune checkpoint lies with the PD-1–PD-L1 axis. Although multiple drugs have been approved, there is uncertainty about patient selection criteria and diagnostic assays. Recent studies related to the laboratory-developed tests have opened up the horizon of PD-1 and PD-L1 immunohistochemistry even at resource-constrained laboratories. We propose to study these immunohistochemistry markers in our laboratory using newer clones.

Materials and Methods We selected 116 consecutive cases of transurethral bladder tumor resection from our laboratory archive and applied PD-1 and PD-L1 immunohistochemistry. The study was approved by the institution's ethics committee.

Results We found high expression of PD-1 and PD-L1 in urothelial carcinoma even with different cut-offs of PD-L1. Muscle invasion, lamina invasion, and grade of carcinoma had a statistically significant effect on the expression; however, age and sex did not affect the expression.

Conclusion Based on our current study, we can conclude that the clones used in our study show high expression in urothelial carcinoma and can aid in patient selection and treatment protocol, irrespective of age and sex.

Keywords

immune checkpoint inhibitors - PD-1 - PD-L1 - urothelial carcinoma

Authors' Contributions

Utpal Kumar contributed to the concept, data collection, literature search, Immunohistochemistry, primary manuscript, and editing of the final manuscript. Michael Leonard Anthony contributed to the concept, data collection, and editing of the final manuscript. Rishabh Sahai contributed to the concept, data collection, literature search, immunohistochemistry, and editing of the final manuscript. Ankur Mittal contributed to the concept, data collection, and editing of the final manuscript. Prashant Durgapal contributed to the concept, primary reporting, primary manuscript, and editing of the final manuscript. Sanjeev Kishore contributed to the concept, primary reporting, scholarly inputs. and editing of the final manuscript.

Institutional Ethics Committee Approval

The study was approved by the Institution's Ethics Committee (approval no: AIIMS/IEC/20/185).

Publikationsverlauf

Artikel online veröffentlicht:
10. November 2021

• References

• 1 Stenehjem DD, Tran D, Nkrumah MA, Gupta S. PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer. OncoTargets Ther 2018; 11: 5973-5989
• 2 U.S. Food & Drug. List of cleared or approved companion diagnostic devices (in vitro and imaging tools) | FDA [Internet]. [cited 2020 Jun 2]. Accessed September 23, 2021 at: https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools
• 3 Cheung CC, Barnes P, Bigras G. et al; Canadian Association of Pathologists-Association Canadienne Des Pathologistes' National Standards Committee for High Complexity Testing (CAP-ACP NSCHCT). Fit-for-purpose PD-L1 biomarker testing for patient selection in immuno-oncology: guidelines for clinical laboratories from the Canadian Association of Pathologists-Association Canadienne Des Pathologistes (CAP-ACP). Appl Immunohistochem Mol Morphol 2019; 27 (10) 699-714
• 4 Karnik T, Kimler BF, Fan F, Tawfik O. PD-L1 in breast cancer: comparative analysis of 3 different antibodies. Hum Pathol 2018; 72: 28-34
• 5 Zarogoulidis P, Porpodis K, Xatzibougias D, Tsiouda T, Daniilidis D. PD-L1 evaluation with DAKO and BIOCARE antibody for immunotherapy; same coin different faces. Eur Respir J 2019; 54: PA3072
• 6 Kang MJ, Kim KM, Bae JS. et al. Tumor-infiltrating PD1-positive lymphocytes and FoxP3-positive regulatory T cells predict distant metastatic relapse and survival of clear cell renal cell carcinoma. Transl Oncol 2013; 6 (03) 282-289
• 7 Tumeh PC, Harview CL, Yearley JH. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515 (7528): 568-571
• 8 Kawahara T, Ishiguro Y, Ohtake S. et al. PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low-grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer. BMC Urol 2018; 18 (01) 97
• 9 Xylinas E, Robinson BD, Kluth LA. et al. Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder. Eur J Surg Oncol 2014; 40 (01) 121-127
• 10 Le Goux C, Damotte D, Vacher S. et al. Correlation between messenger RNA expression and protein expression of immune checkpoint-associated molecules in bladder urothelial carcinoma: a retrospective study. Urol Oncol 2017; 35 (05) 257-263
• 11 Owen D, Chu B, Lehman AM. et al. Expression patterns, prognostic value, and intratumoral heterogeneity of PD-L1 and PD-1 in thymoma and thymic carcinoma. J Thorac Oncol 2018; 13 (08) 1204-1212
• 12 Wang B, Pan W, Yang M. et al. Programmed death ligand-1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder. Cancer Sci 2019; 110 (02) 489-498
• 13 Pichler R, Fritz J, Lackner F. et al. Prognostic value of testing PD-L1 expression after radical cystectomy in high-risk patients. Clin Genitourin Cancer 2018; 16 (05) e1015-e1024
• 14 Li Q, Li F, Che J, Zhao Y, Qiao C. Expression of B7 homolog 1 (B7H1) is associated with clinicopathologic features in urothelial bladder cancer. Med Sci Monit 2018; 24: 7303-7308
• 15 Wang Y, Zhuang Q, Zhou S, Hu Z, Lan R. Costimulatory molecule B7-H1 on the immune escape of bladder cancer and its clinical significance. J Huazhong Univ Sci Technolog Med Sci 2009; 29 (01) 77-79
• 16 Ding X, Chen Q, Yang Z. et al. Clinicopathological and prognostic value of PD-L1 in urothelial carcinoma: a meta-analysis. Cancer Manag Res 2019; 11: 4171-4184
• 17 Holland BC, Sood A, Delfino K. et al. Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy. Cancer Immunol Immunother 2019; 68 (06) 991-997
• 18 Zajac M, Ye J, Mukhopadhyay P. et al. Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy. PLoS One 2020; 15 (04) e0231936
• 19 Plimack ER, Bellmunt J, Gupta S. et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 2015; 33 (15_suppl): 4502-4502
• 20 Massard C, Gordon MS, Sharma S. et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 2016; 34 (26) 3119-3125
• 21 Eckstein M, Erben P, Kriegmair MC. et al. Performance of the Food and Drug Administration/EMA-approved programmed cell death ligand-1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab. Eur J Cancer 2019; 106: 234-243