PMN and anti-tumor immunity-The case of bladder cancer immunotherapy

Urothelial carcinoma of the bladder accounts for ~5% of all cancer deaths in humans. The majority of bladder tumors are non-muscle invasive at diagnosis, and there is a high rate of tumor 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 been the treatment of choice for non-muscle invasive bladder cancer. Despite nearly 40 years of clinical use, the mechanism(s) by which intravesical administration of BCG results in elimination of bladder tumors remains undefined. Granulocytes (polymorphonuclear neutrophils (PMN)) are the predominant immune cell (in number) that enters the bladder after BCG installation, and a number of studies have highlighted the importance of PMN in the antitumor activity of BCG. Studies from our laboratory demonstrated presence of intracellular stores of the apoptosis-inducing protein TNF-related apoptosis-inducing ligand (TRAIL) in PMN that are rapidly released after interaction with BCG cell wall components, along with a correlation between increased urinary levels of TRAIL and BCG responsiveness. Mature PMN in circulation are terminally differentiated cells with limited biosynthetic capacity, so the proteins located in the distinct PMN granule populations are compartmentalized concomitant with their synthesis during myelopoiesis. Thus, understanding PMN production, localization, and release of TRAIL is important in the design of future BCG-based bladder tumor immunotherapy protocols.