Prostate cancer ranks second to lung cancer in terms of annual mortality among men in the United States. The mainstay of therapy for advanced prostate cancer, unchanged since 1941, continues to be palliative androgen deprivation. As such, more effective treatments of prostate cancer are urgently needed. In this respect, immunotherapy could offer an important alternative or adjunct to current therapy.

T cells of the immune system are the major combatants against cancers. One of the major goals of immunologic approaches for the treatment of cancer is the induction of cancer-specific T cell responses of sufficient magnitude to eliminate the cancer and prevent its recurrence. Despite some successful attempts by different workers in this area, tumor immunotherapy remains largely anecdotal and the collective experience has been frustrating. One reason for this less-than-optimal outcome is that, until recently, there was insufficient knowledge of normal regulatory processes that limit T cell function.

B7/CD28 family molecules control activation and function of T cells. We and others have discovered new members of the B7 family including B7x and B7-H3 and found that B7x inhibits T cell function. We have recently completed a comprehensive investigation of B7 family molecules in a cohort of 823 patients who underwent prostatectomy for prostate cancer and have been followed for more than 7 years. This study revealed that patients with strong tumor B7x and B7-H3 expression were more likely to have disease spread at the time of surgery, and increased risk of cancer recurrence and cancer-specific death. These observations suggested that B7x and B7-H3 are exploited by prostate cancer as an immune evasion pathway to inhibit T cell function. Therefore, we have hypothesized that blockade of B7x and B7-H3 generates therapeutic tumor immunity against prostate cancer. We have generated a number of important new tools that provide us with unique opportunities to develop a new prostate cancer immunotherapeutic strategy by enhancing T cell functions via blockade of the B7x and B7-H3 pathways.

The proposal is directly related to the main objectives of "Therapy" of the Prostate Cancer Research Program. The results from this proposal will have a significant impact on the concepts or methods that drive the field and make an original contribution to the goal of cure of prostate cancer. The proposed research is significant, because it is anticipated to provide new targets for therapeutic interventions that will aid the growing numbers of prostate cancer patients. In addition, it is expected that the proposed research will fundamentally advance the fields of T cell coinhibition in cancer.