Immune Exclusion Is Frequent in Small-Cell Carcinoma of the Bladder

Small-cell cancer of the urinary bladder is a rare but highly aggressive disease. It is currently unclear whether immune checkpoint therapies that have been approved for urothelial carcinomas will also be efficient in small-cell carcinomas. In this study, we analyzed potential predictors of response including PD-L1 expression and the quantity and location of tumor-infiltrating lymphocytes (TILs) in 12 small-cell and 69 “classical” urothelial cancers by immunohistochemistry. The analysis revealed that small-cell carcinomas were characterized by the virtual absence of PD-L1 expression and an “immune-excluded” phenotype with only a few TILs in the center of the tumor (CT). In small-cell carcinomas, the average immune cell density in the CT (CD3: 159±206 , CD8: 87±169 cells/mm2) was more than 3 times lower than that in the urothelial carcinomas (CD3: 625±800 , p<0.001 ; CD8: 362±626 cells/mm2, p=0.004 ) while there was no significant difference in the immune cell density at the invasive margin (IM) (small-cell carcinomas CD3: 899±733 , CD8: 404±433 cells/mm2; urothelial carcinomas CD3: 1167±1206 , p=0.31 ; CD8: 582±864 cells/mm2, p=0.27 ). Positive PD-L1 staining was found in 39% of urothelial cancers, but in only 8% of small-cell bladder cancer cases ( p=0.04 ). Concordant with these data, a sharp decrease of PD-L1 positivity from >80% to 0% positive cells and of TILS in the CT from 466-1063 CD3-positive cells/mm2 to 50-109 CD3-positive cells/mm2 was observed in two cancers with clear-cut progression from “classical” urothelial to small-cell carcinoma. In conclusion, these data demonstrate that small-cell bladder cancer commonly exhibits an immune-excluded phenotype.