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      Expression patterns of the immune checkpoint ligand CD276 in urothelial carcinoma

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          Abstract

          Background

          CD276 is an immune checkpoint molecule. Elevated CD276 expression by urothelial carcinoma is associated with poor prognosis, but little is known about its expression across different tumor stages. We therefore investigated CD276 expression in bladder cancer (BC) cells and in tissue samples of BC stages from pT2 to pT4.

          Methods

          CD276 expression was explored in 4 urothelial cancer cell lines and 4 primary normal urothelial cell populations by quantitative RT-PCR, Western blot and flow cytometry. CD276 was investigated in bladder tumors from 98 patients by immunohistochemistry using a score (0–300) incorporating both, staining intensity and area of CD276 staining. Normal appearing urothelium in the bladder of the same patients served as controls.

          Results

          The urothelial carcinoma cell lines expressed significantly higher levels of CD276 on transcript ( p < 0.006), total protein levels ( p < 0.005), and on the cell surface ( p < 0.02) when compared to normal urothelial cells. In pT2–T4 tumor tissue samples, CD276 was overexpressed (median score 185) when compared to corresponding healthy tissues from the same patients (median score 50; p < 0.001). No significant differences in CD276 expression were recorded in late, locally advanced ≥ pT3a tumors (median score 185) versus organ-confined < pT3a tumors (median score 190), but it was significantly lower in the normal urothelial tissue associated with ≥ pT3a tumors (median score 40) versus < pT3a tumors (median score 80; p < 0.05).

          Conclusion

          CD276 expression is significantly elevated in urothelial carcinoma cells in all stages but varies between individuals considerably. Reduced CD276 expression in normal urothelial cells may imply that these cells would be protected from CD276-mediated immuno therapies.

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          Most cited references 25

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          Cancer statistics, 2019

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.
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            Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

            New England Journal of Medicine, 376(11), 1015-1026
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              Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

              First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.
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                Author and article information

                Contributors
                aicher@uni-tuebingen.de
                Journal
                BMC Urol
                BMC Urol
                BMC Urology
                BioMed Central (London )
                1471-2490
                12 April 2021
                12 April 2021
                2021
                : 21
                Affiliations
                [1 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Department of Urology, , University of Tuebingen Hospital, ; Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany
                [2 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Vancouver Prostate Centre, , University of British Columbia, ; Level 6, 2775 Laurel St, Vancouver, BC V5Z 1M9 Canada
                [3 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Department of Urology, Center for Medical Research, , University of Tuebingen Hospital, ; Waldhoernlestrasse 22, 72072 Tübingen, Germany
                Article
                829
                10.1186/s12894-021-00829-0
                8042686
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: Adolf-Leuze-Stiftung, Stiftungsnetzwerk Region Stuttgart
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Urology

                urothelial carcinoma, immune check-point protein, cd276, b7-h3, bladder tumor stages

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