Myeloid-derived suppressor cells are essential partners for immune checkpoint inhibitors in the treatment of cisplatin-resistant bladder cancer.

Myeloid-derived suppressor cells (MDSCs) are one of the key players that contribute to immune evasion. The purpose of the present study was to investigate whether MDSCs could be a novel target for the treatment of cisplatin-resistant bladder cancer. We established cisplatin-resistant bladder cancer cell lines (MB49R, MBT-2R, and T24R) and evaluated chemokine expression and MDSC expansion. We also assessed the antitumor effect by depleting MDSCs with or without a α-PD-L1 antibody using MB49R xenograft models. The chemokine expression of CXCL1, CXCL2, and CCL2 increased in cisplatin-resistant cells compared to those in their parent strains. Monocytic MDSCs (Mo-MDSCs) were observed more frequently compared to polymorphonuclear MDSCs (PMN-MDSCs) in MB49R tumors. The immunosuppressive genes arginase 1 and iNOS were comparably expressed in each MDSC subtype. In vivo, combination therapy targeting both PMN- and Mo-MDSCs using α-Gr1 and α-Ly6C antibodies significantly reduced tumor volume with increased infiltration of CD8 T cells in the tumor. Finally, co-targeting pan-MDSCs and PD-L1 remarkably reduced the tumor growth. These findings suggest that targeting MDSCs might enhance the therapeutic effect of immune checkpoint inhibitors in cisplatin-resistant bladder cancers.

Steroid sulfatase promotes invasion through epithelial-mesenchymal transition and predicts the progression of bladder cancer.

Androgen signal has been recently suggested to be associated with the progression of bladder cancer. Steroid sulfatase (STS) is a steroid sulfate activation enzyme, considered to be one of the key enzymes in the androgen signaling pathway. However, the role of STS in bladder cancer has not been elucidated. The purpose of the present study was to determine the clinical and functional significance of STS in bladder cancer. Immunohistochemical analysis of surgical specimens obtained by radical cystectomy (n=114) demonstrated that overexpression of STS was associated with the invasion of bladder cancer, as evidenced by the incidence of STS-positive cancers (11.5 and 37.1% in non-muscle invasive and muscle invasive bladder cancers, respectively; P=0.003). STS-positive cancer demonstrated shorter recurrence-free survival and cancer-specific survival (P=0.0027 and 0.0030, respectively). Furthermore, knockdown of STS significantly reduced cell migration and invasion capacities of bladder cancer cells (P<0.001 and P=0.005, respectively), accompanied by the upregulation of E-cadherin and downregulation of vimentin. In summary, the present study demonstrated that STS promotes the invasion capability of bladder cancer via regulation of the epithelial-mesenchymal transition, and may be a useful marker for predicting the progression of bladder cancers.

Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy.

Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.

Oncological outcomes classified according to metastatic lesions in the era of molecular targeted drugs for metastatic renal cancer.

Since the introduction of molecular targeted agents for the treatment of metastatic renal cell cancer (mRCC), several treatment outcomes, including those from our facilities, have been reported. However, the outcome of these drugs, classified by the metastatic organs, is not well known. The present study reported the treatment results of molecular-targeted agents as classified by the metastatic organ at Osaka City University Graduate School of Medicine. A total of 180 consecutively treated patients who had received molecular targeted agents for metastatic renal cancer for 3 or more months were retrospectively analyzed. The overall survival was calculated and compared according to the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, the number of metastatic organs, and metastatic lesions. The median overall survival of patients with mRCC treated by molecular targeted agents was 34 months. A significant difference in survival rate between groups was found according to the MSKCC criteria. Patients with single metastatic organ lived significantly longer compared with those with metastases in multiple organs. Patients with pancreatic metastasis had a good response to molecular targeted drugs. Pancreatic metastasis, the number of metastatic organs, and MSKCC criteria were independent risk factors for overall survival. Treatment of mRCC by molecularly targeted agents did not show any difference by metastatic organs except for the pancreas, although its efficacy depends on the number of metastatic organs and the MSKCC classification.

A Case of Metastatic Urachal Carcinoma Treated With FOLFIRI (irinotecan and 5-Fluorouracil/leucovorin) Plus Bevacizumab.

A 68-year-old man was introduced to our hospital for the treatment of lung and mediastinum lymph node metastases that originated from an urachal carcinoma 4 years after a partial cystectomy. First-line chemotherapy with an S-1 and cisplatin combination was ineffective. The patient received FOLFIRI plus bevacizumab chemotherapy as salvage chemotherapy. Stability was achieved after eight cycles of FOLFIRI plus bevacizumab therapy. We conducted a biopsy of the metastatic tumor, and the pathology of the biopsy tissue was partially necrotic. To our knowledge, this case represents the first report of a metastatic urachal carcinoma treated with FOLFIRI plus bevacizumab.

A Case of Pulmonary Pleomorphic Carcinoma With Renal Metastasis.

A 62-year-old man was referred to our hospital for an axillary mass. Computed tomography (CT) revealed a right axillary tumor and a left renal tumor. Needle biopsies of lung tumor and renal tumor were performed, but a definite diagnosis was impossible. Because his performance status worsened and the lung tumor grew day by day, chemotherapy with gemcitabine and cisplatin was started without definite diagnosis. However, the chemotherapy could not be continued because of interstitial pneumonia and the patient died because of the progression of disease. The final histopathologic diagnosis was pulmonary pleomorphic carcinoma based on immunohistochemical staining.