open access
The type of distribution of PD-L1 positive immune cells and PD-L1 expression in tumor cells correlate with the development of non-classical differentiation in urinary bladder cancer
Affiliations- Department of Tumour Pathology and Pathomorphology, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, Izabeli Romanowskiej 2, 85-796 Bydgoszcz, Poland
- Department of Clinical Pathomorphology, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
- Department of Tumour Pathology and Pathomorphology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
open access
Abstract
Background: The basic diagnostic tool of urinary bladder cancer is the histopathological assessment.
However, it is insufficient to accurately predict the progression of this disease. There is a need to look
for new prognostic factors that will make the therapeutic process more effective. The aim of this study is
to evaluate the effect of activation of a PD1 – PD-L1 immune checkpoint in immune effector cells (IECs)
and tumor cells, on the development of malignancy in the form of non-classic differentiation in urinary
bladder cancer.
Materials and methods: 110 patients with stage pT1-pT4 urothelial bladder carcinoma who underwent radical
cystectomy/cystoprostatectomy between 2011 and 2014 were included in the study. Tumor advancement
(pT stage), grade (G), as well as, non-classic differentiation frequency and number were evaluated pathologically.
In each case, the area of the tumor containing PD-L1+ IECs was analyzed. The distribution of
PD-L1+ immune effector cells within the tumor was also assessed as dispersed or aggregated.
Results: The frequency of non-classic differentiation was significantly lower in urothelial bladder cancer
tumors with a dispersed pattern of distribution of PD-L1+ IECs. A correlation between the extent of PD-L1
expression in tumor cells and the non-classic differentiation number in UBC was identified.
Conclusions: The distribution of cells expressing the immune checkpoint biomarker PD-L1 constitutes a
new prognostic factor and may play a key role in the selection of individualized immunotherapy. In addition,
the evaluation of non-classic differentiation in the tumor may complement the assessment of PD-L1
expression due to its capacity to characterize the current malignant potential of the tumor, whereas the
assessment of extent and distribution of PD-L1+ in tumor-associated immune cells indicates the functional
status of the immune system.
Abstract
Background: The basic diagnostic tool of urinary bladder cancer is the histopathological assessment.
However, it is insufficient to accurately predict the progression of this disease. There is a need to look
for new prognostic factors that will make the therapeutic process more effective. The aim of this study is
to evaluate the effect of activation of a PD1 – PD-L1 immune checkpoint in immune effector cells (IECs)
and tumor cells, on the development of malignancy in the form of non-classic differentiation in urinary
bladder cancer.
Materials and methods: 110 patients with stage pT1-pT4 urothelial bladder carcinoma who underwent radical
cystectomy/cystoprostatectomy between 2011 and 2014 were included in the study. Tumor advancement
(pT stage), grade (G), as well as, non-classic differentiation frequency and number were evaluated pathologically.
In each case, the area of the tumor containing PD-L1+ IECs was analyzed. The distribution of
PD-L1+ immune effector cells within the tumor was also assessed as dispersed or aggregated.
Results: The frequency of non-classic differentiation was significantly lower in urothelial bladder cancer
tumors with a dispersed pattern of distribution of PD-L1+ IECs. A correlation between the extent of PD-L1
expression in tumor cells and the non-classic differentiation number in UBC was identified.
Conclusions: The distribution of cells expressing the immune checkpoint biomarker PD-L1 constitutes a
new prognostic factor and may play a key role in the selection of individualized immunotherapy. In addition,
the evaluation of non-classic differentiation in the tumor may complement the assessment of PD-L1
expression due to its capacity to characterize the current malignant potential of the tumor, whereas the
assessment of extent and distribution of PD-L1+ in tumor-associated immune cells indicates the functional
status of the immune system.
Keywords
PD-L1; urothelial bladder cancer; tumor microenvironment; immune cell, NDN, immune effector cells, IEC, immunological control point distribution, ICPD
About this articleTitle
The type of distribution of PD-L1 positive immune cells and PD-L1 expression in tumor cells correlate with the development of non-classical differentiation in urinary bladder cancer
Journal
Issue
Article type
Original article
Pages
136-141
Published online
2019-05-24
Page views
479
Article views/downloads
644
DOI
Bibliographic record
Medical Research Journal 2019;4(3):136-141.
Keywords
PD-L1
urothelial bladder cancer
tumor microenvironment
immune cell
NDN
immune effector cells
IEC
immunological control point distribution
ICPD
Authors
Mateusz Matusiak
Jarosław Starzyński
Jakub Jóźwicki
Jakub Dzierżawski
Jan Misiak
Wojciech Jóźwicki
References (28)- Bellmunt J, Orsola A, Leow JJ, et al. ESMO Guidelines Working Group. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3: iii40–iii48.
- Crundwell M. Pathology and genetics of tumours of the urinary system and male genital organs. BJU International. 2004; 94(4): 675–675.
- Jozwicki W, Domaniewski J, Skok Z, et al. Usefulness of histologic homogeneity estimation of muscle-invasive urinary bladder cancer in an individual prognosis: a mapping study. Urology. 2005; 66(5): 1122–1126.
- Domanowska E, Jozwicki W, Domaniewski J, et al. Muscle-invasive urothelial cell carcinoma of the human bladder: multidirectional differentiation and ability to metastasize. Hum Pathol. 2007; 38(5): 741–746.
- Jóźwicki W, Brożyna AA, Siekiera J, et al. Frequency of CD4+CD25+Foxp3+ cells in peripheral blood in relation to urinary bladder cancer malignancy indicators before and after surgical removal. Oncotarget. 2016; 7(10): 11450–11462.
- Jóźwicki W, Brożyna AA, Siekiera J, et al. Expression of RCAS1 correlates with urothelial bladder cancer malignancy. Int J Mol Sci. 2015; 16(2): 3783–3803.
- Jóźwicki W, Brożyna AA, Siekiera J. Expression of OCT4A: the first step to the next stage of urothelial bladder cancer progression. Int J Mol Sci. 2014; 15(9): 16069–16082.
- Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015; 348(6230): 56–61.
- Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007; 19(7): 813–824.
- Szabados B, van Dijk N, Tang YZ, et al. Response Rate to Chemotherapy After Immune Checkpoint Inhibition in Metastatic Urothelial Cancer. Eur Urol. 2018; 73(2): 149–152.
- Jóźwicki W, Skok Z, Brożyna A, et al. Urological Oncology Prognostic and diagnostic implications of histological differentiation in invasive urothelial cell carcinoma of the bladder: variant or non-classic differentiation number. Central European Journal of Urology. 2010; 63: 112–116.
- Jóźwicki W. VENTANA PD-L1 (SP142) - principles of pathomorphological evaluation in urinary bladder cancer. ; 2017.
- Kim SP, Frank I, Cheville JC, et al. The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. J Urol. 2012; 188(2): 405–409.
- Huang Y, Zhang SD, McCrudden C, et al. The prognostic significance of PD-L1 in bladder cancer. Oncol Rep. 2015; 33(6): 3075–3084.
- Tzeng A, Diaz-Montero CM, Rayman PA, et al. Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma. Target Oncol. 2018; 13(5): 599–609.
- 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(5): e1015–e1024.
- Driver BR, Miller RA, Miller T, et al. Programmed Death Ligand-1 (PD-L1) Expression in Either Tumor Cells or Tumor-Infiltrating Immune Cells Correlates With Solid and High-Grade Lung Adenocarcinomas. Arch Pathol Lab Med. 2017; 141(11): 1529–1532.
- El Jabbour T, Ross JS, Sheehan CE, et al. PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry. J Clin Pathol. 2018; 71(1): 46–51.
- Faraj SF, Munari E, Guner G, et al. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology. 2015; 85(3): 703.e1–703.e6.
- Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031): 1909–1920.
- Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014; 515(7528): 558–562.
- Markowitz GJ, Havel LS, Crowley MJp, et al. Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. JCI Insight. 2018; 3(13).
- Ohaegbulam KC, Assal A, Lazar-Molnar E, et al. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015; 21(1): 24–33.
- Bellmunt J, de Wit R, Vaughn DJ, et al. KEYNOTE-045 Investigators. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017; 376(11): 1015–1026.
- Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 2017; 18(2): 212–220.
- Zhang X, Shi X, Li J, et al. PD-1 Blockade Overcomes Adaptive Immune Resistance in Treatment with Anchored-GM-CSF Bladder Cancer Cells Vaccine. J Cancer. 2018; 9(23): 4374–4381.
- de Jong JJ, Stoop H, Nieboer D, et al. Concordance of PD-L1 expression in matched urothelial bladder cancer specimens. Histopathology. 2018; 73(6): 983–989.
- He J, Hu Y, Hu M, et al. Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer. Sci Rep. 2015; 5: 13110.