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Clinical Impact of the Increase in Immunosuppressive Cell-Related Gene Expression in Urine Sediment during Intravesical Bacillus Calmette-Guérin

1
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara-shi, Nara 634-8522, Japan
2
Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara-shi, Nara 634-8522, Japan
*
Author to whom correspondence should be addressed.
Diseases 2019, 7(2), 44; https://doi.org/10.3390/diseases7020044
Received: 19 April 2019 / Revised: 8 June 2019 / Accepted: 17 June 2019 / Published: 18 June 2019
(This article belongs to the Section Oncology)
Background: The aim of this study is to evaluate the clinical impact of intravesical Bacillus Calmette-Guérin (BCG)-induced changes in blood/urinary immune markers. Methods: Time-course changes in blood/urinary clinical parameters and mRNA expression of 13 genes in urine sediment taken eight times during the treatment course of intravesical BCG (before, every 2 weeks for 8 weeks, and after) in 24 patients with non-muscle invasive bladder cancer. The genes examined include cellular markers of four immune checkpoint proteins (PD-L1, PD-L2, PD-1, and CTLA-4), immunosuppressive cells (regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells), pan-T lymphocytes, B lymphocytes, and neutrophils. Results: Significant transient increase in gene expression was observed for PD-L1, PD-1, FOXP3, and CD204 at 6–8 doses of BCG. The patients were stratified into two groups depending on the number of genes with increased mRNA expression. Fourteen (58%) had 0–1 genes upregulated, while 10 (42%) had 2–4 genes with increased expression. No patient in the 0–1 group experienced recurrence, while 70% of patients in the 2–4 group experienced recurrence (p value = 0.037, hazard ratio = 5.93). Conclusions: Our findings suggested that increases in more than one of PD-L1, PD-1, FOXP3, and CD204, expression in the urine sediments was associated with resistance to BCG treatment. View Full-Text
Keywords: Bacillus Calmette-Guérin; non-muscle invasive bladder cancer; tumor-associated macrophage; regulatory T cell; myeloid-derived suppressor cell; intravesical recurrence Bacillus Calmette-Guérin; non-muscle invasive bladder cancer; tumor-associated macrophage; regulatory T cell; myeloid-derived suppressor cell; intravesical recurrence
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Miyake, M.; Hori, S.; Ohnishi, S.; Owari, T.; Iida, K.; Ohnishi, K.; Morizawa, Y.; Gotoh, D.; Itami, Y.; Nakai, Y.; Inoue, T.; Anai, S.; Torimoto, K.; Aoki, K.; Fujii, T.; Tanaka, N.; Fujimoto, K. Clinical Impact of the Increase in Immunosuppressive Cell-Related Gene Expression in Urine Sediment during Intravesical Bacillus Calmette-Guérin. Diseases 2019, 7, 44.

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