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Open AccessArticle

Patient-Derived Non-Muscular Invasive Bladder Cancer Xenografts of Main Molecular Subtypes of the Tumor for Anti-Pd-l1 Treatment Assessment

1
Department of Pathology, Department of Operative Surgery and Clinical Anatomy, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
2
Department of Oncology, Laboratory of Pharmacology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
3
Department of Oncological Urology, Russian National Research Medical Center of Radiology, 3 2nd Botkinsky Proezd, 125284 Moscow, Russia
4
Laboratory of Molecular Pharmacology, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraja Kupavna, Russia
*
Author to whom correspondence should be addressed.
Cells 2019, 8(6), 526; https://doi.org/10.3390/cells8060526
Received: 25 April 2019 / Revised: 20 May 2019 / Accepted: 29 May 2019 / Published: 31 May 2019
Background: Establishment of heterotopic patient-derived xenografts of primary and relapsed non-muscular invasive bladder cancer (NMIBC) to explore the biological property of PD-L1 signaling that may impact bladder tumor growth in humanized animals. Methods: Tumor cells of luminal, basal, and p53 subtypes of primary and relapsed NMIBC were engrafted to irradiated (3.5 Gy) NOG/SCID female mice along with intraperitoneal transplantation of human lymphocytes (5 × 107 cells/mouse); a role of PD-L1 signaling pathway inhibition for bladder cancer growth was assessed in humanized animals that carried PD-L1-expressing main molecular subtypes of bladder carcinoma patient-derived xenografts (PDX) and provided with selective anti-PD-L1 treatment. We used two-tailed Student’s t test to explore differences between main and control subgroups. Significance of intergroup comparison was measured with one-way ANOVA followed by the Tukey’s or Newman–Keul’s criterion. Survival curves were analyzed with the Gehan’s criterion with the Yate’s correction. The Spearman’s correlation was used to assess the link between CD8+ expression and sPD-L1 serum level. Differences were considered statistically significant at p < 0.05. Results: Heterotopic primary and relapsed luminal, basal, and p53 subtypes of NMIBC PDXs were established. More than 25% of counted tumor cells of all PDX specimens expressed PD-L1, so the tumors were ranged as PD-L1 positive. Anti-PD-L1 intervention increased survival of the animals that carried both primary and relapsed luminal noninvasive, muscular invasive, and relapsed luminal bladder cancer xenografts. There was significant retardation of tumor volume duplication time in aforementioned subgroups correlated with PD-L1 expression. Bad response of p53 mutant subtypes of NMIBC on specific anti-PD-L1 treatment may be associated with low CD8+ cells representation into the tumors tissue. Conclusions: Established PD-L1-positive NMIBC PDXs differently replied on anti-PD-L1 treatment due to both NMIBC molecular subtype and tumor T-suppressors population. The results may have major implications for further clinical investigations. View Full-Text
Keywords: non-muscular invasive bladder cancer; patient-derived xenograft; anti-PD-L1 treatment; metastasis; molecular subtypes non-muscular invasive bladder cancer; patient-derived xenograft; anti-PD-L1 treatment; metastasis; molecular subtypes
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Blinova, E.; Roshchin, D.; Kogan, E.; Samishina, E.; Demura, T.; Deryabina, O.; Suslova, I.; Blinov, D.; Zhdanov, P.; Osmanov, U.; Nelipa, M.; Kaprin, A. Patient-Derived Non-Muscular Invasive Bladder Cancer Xenografts of Main Molecular Subtypes of the Tumor for Anti-Pd-l1 Treatment Assessment. Cells 2019, 8, 526.

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