The role of neutrophils and TRAIL in BCG immunotherapy for bladder cancer

Urothelial carcinoma of the bladder accounts for approximately 5% of all cancer deaths in humans. Most bladder tumors are non-muscle invasive at diagnosis and have a high rate of local recurrence and progression even after local surgical therapy. Thus, many patients require lifelong follow-up examinations that include additional prophylactic treatments in the event of recurrence. Since its first use in 1976, Mycobacterium bovis bacillus Calmette-Guerin (BCG) has become the treatment of choice for non-muscle invasive bladder cancer. Despite over 30 years of clinical use, the anticancer mechanism of BCG in the treatment of bladder cancer has not been clearly defined. Studies from our laboratory have demonstrated a correlation between increased urinary levels of the apoptosis-inducing protein TNF-related apoptosis-inducing ligand (TRAIL) and BCG responsiveness, as well as the presence of intracellular stores of TRAIL in polymorphonuclear neutrophils (PMN) that are rapidly released after interaction with BCG cell wall components. Mature PMN in circulation operate to a great extent as terminally differentiated cells with limited biosynthetic capacity. Proteins located in the three distinct granule populations of mature PMN are compartmentalized concomitant with their synthesis during cell maturation, rather than being differentially segregated by localizing markers that target a specific protein to a particular granule. Thus, understanding PMN production, localization, and release of TRAIL is important in the design of future BCG-based bladder tumor immunotherapy protocols.