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. 2019 May 31;8(6):526.
doi: 10.3390/cells8060526.

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

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Free PMC article

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

Ekaterina Blinova et al. Cells. .
Free PMC article

Abstract

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.

Keywords: anti-PD-L1 treatment; metastasis; molecular subtypes; non-muscular invasive bladder cancer; patient-derived xenograft.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) PD-L1 expression in bladder cancer PDXs in dependence on PD-L1 treatment; PD-L1 expression as scatterplots of individual % of positively stained tumor cells with estimated median for maternal tumor used for engraftment (I), for PDX of control subgroup mice (II), and animals (III) utilized specific therapy (n = 20 in maternal tumor group; n = 10 in each subgroup); xp < 0.05 when compared with control (Student’s t-test). (B) PD-L1-positive staining of primary luminal (1), basal (2), and p53 subtypes (3) of NMIBC, and relapsed luminal (4), basal (5), and p53 (6) subtypes of bladder cancer in maternal tumor’s specimens; IHC staining, x600.
Figure 1
Figure 1
(A) PD-L1 expression in bladder cancer PDXs in dependence on PD-L1 treatment; PD-L1 expression as scatterplots of individual % of positively stained tumor cells with estimated median for maternal tumor used for engraftment (I), for PDX of control subgroup mice (II), and animals (III) utilized specific therapy (n = 20 in maternal tumor group; n = 10 in each subgroup); xp < 0.05 when compared with control (Student’s t-test). (B) PD-L1-positive staining of primary luminal (1), basal (2), and p53 subtypes (3) of NMIBC, and relapsed luminal (4), basal (5), and p53 (6) subtypes of bladder cancer in maternal tumor’s specimens; IHC staining, x600.
Figure 2
Figure 2
(A) Average survival of animals in experimental groups; average survival (n = 10) presented in days of life (scatterplots and median); ÷ p < 0.05 when compared with control (Gehan’s criterion with Yates’s correction). (B) Expression of GATA 3 (1, 4, 7, and 10), KRT 5/6 (2, 5, 8, and 11), and p53 (3, 6, 9, and 12) in maternal tumor’s specimens and in established PDX’s ones; IHC staining, ×600.
Figure 2
Figure 2
(A) Average survival of animals in experimental groups; average survival (n = 10) presented in days of life (scatterplots and median); ÷ p < 0.05 when compared with control (Gehan’s criterion with Yates’s correction). (B) Expression of GATA 3 (1, 4, 7, and 10), KRT 5/6 (2, 5, 8, and 11), and p53 (3, 6, 9, and 12) in maternal tumor’s specimens and in established PDX’s ones; IHC staining, ×600.
Figure 3
Figure 3
CD8+ population of T cells in PDX’s tumor specimens of mice utilized anti-PD-L1 specific treatment. IHC staining, ×600.
Figure 3
Figure 3
CD8+ population of T cells in PDX’s tumor specimens of mice utilized anti-PD-L1 specific treatment. IHC staining, ×600.

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