TRAIL: A MECHANISM FOR BCG-INDUCED ANTI-TUMOR ACTIVITY IN BLADDER CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urothelial carcinoma of the bladder accounts for approximately 5% of all cancer deaths in humans. Current treatments extend time to recurrence but do not alter disease survival. since 1976, Mycobacterium bovis vacillus Calmette-Guerin (BCG) has been used with increased success to treat superficial bladder cancer, and is the treatment of choice for this tumor entity. Surprisingly, the antitumor effector mechanisms remain elusive. BCG immunotherapy results in a massive local immune response characterized by the induced expression of Th-1 cytokines (e.g., IL-2, IL-12, IFN-y) in the urine and bladder tissue, and by an influx of granulocytes and mononuclear cells into the bladder wall. We are especially interested in IFN-y produced in this clinical setting, because IFN-y stimulates on multiple immune cell types the expression of TNF-related apoptosis-inducing ligand (TRAIL), a TNF family member that induces apoptosis in a variety of tumor cell types but has little or no cytotoxicity against normal cells. Recent studies by our group demonstrated for the first time that TRAIL is induced during BCG treatment. Urine TRAIL levels correlated with effective therapy, suggesting a link to antitumor activity. Moreover, TRAIL was expressed on voided neutrophils during the time period examined (3-5 H post instillation). These investigators hypothesize that BCG treatment of superficial bladder cancer induces TRAIL expression on infiltrating inflammatory cells, especially neutorphils, which is a necessary effector molecule for a favorable therapeutic outcome. Thus, this proposal describes studies that will evaluate clinical samples from bladder cancer patients undergoing BCG therapy to substantiate the role of TRAIL.