The incidence and mortality rates of prostate cancer vary substantially among different geographic areas and ethnic groups. Notably, African-American men have the highest risk of developing prostate cancer and, due to a more aggressive type of the disease, their mortality rate is twice that of European-American men. While socioeconomic factors contribute to this health disparity, these factors do not fully explain the differences in prostate cancer incidence, aggressiveness, and mortality among different ethnic groups in the U.S. We hypothesized that gene expression profiles of prostate tumors from African-American and European-American men may reveal biological differences between the two groups that could explain the more aggressive cancer phenotype in African-American men. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level, comparing these patients. Our analysis revealed a significant number of genes to be differently expressed among the two patient groups. Using disease association analysis, we identified a relationship among these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level, with numerous differently expressed genes clustering in the immune and stress response, cytokine signaling, and chemotaxis pathways. Specifically, an interferon gene signature was present in tumors of African-American patients, suggesting involvement of viral infections in disease pathology. In summary, the gene expression profiles of prostate tumors showed prominent differences in tumor immunobiology between African-American and European-American men. The data suggest that prostate tumors from African-American patients may elicit a different immune response when compared with tumors from European-American men. We hypothesize that this heightened immune response in African-American men is a predisposing factor for tumor progression and metastasis. These novel findings could have implications for prostate cancer therapy. Clinical immunotherapy trials for prostate cancer have been conducted and these new therapies may soon enter clinical practice. Our data suggest that African-American and European-American patients might respond differentially to immunotherapy. In addition, the observed differences may offer opportunities for a targeted therapy that is directed towards the immune cells in the cancerous prostate. We do not yet know why prostate tumors from African-American patients have a different immunologic profile than tumors from European-American patients. Possible causes include environmental factors (e.g., infections), genetic factors (e.g., variations in immune regulatory genes), or the interactions of both. In the future, we will examine the involvement of these factors in the tumor biology of African-Americans. Based on these findings, we started two projects exploring the contribution of: 1) viral infections, and 2) intrinsic expression differences in immunoregulatory genes to the existing prostate cancer health disparity between African-American and European-American men. Previous epidemiological studies of prostate cancer indicate the involvement of an infectious agent in its etiology. Candidate causative agents include both known sexually transmitted diseases (e.g., gonorrhoea, syphilis, or chlamydia trachomatis), and viral infections, which may occur either by sexual transmission or independent of it. The hypothesis that infections may cause prostate cancer is also supported by studies that identified two genes involved in innate immunity as candidate prostate cancer susceptibility genes, RNASEL and MSR1. RNASEL is required for the antiviral role of interferons, while MSR1 binds to Gram-negative and Gram-positive bacteria and its loss leads to increased bacterial infections. We hypothesize that viral infectious agents cause the interferon gamma signature in tumors from African-American patients. In a collaboration with the Laboratory of Molecular Technology (SAIC-Frederick, Inc.), we will use a proprietary microarray chip that detects all known mammalian viruses (650). Because of the large number of spotted sequences (10,000) and the coverage of each viral genome by multiple probe sets in conserved regions (10 probesets for the majority of viruses), we should also be able to detect sequences from undiscovered viruses that have significant homologies to known mammalian viruses. If a candidate virus is detected, we will perform probe rescue experiments to capture and sequence the cDNA, and then proceed with in situ hybridization to identify the location of the virus and show that it is present in prostate tumors with an epithelial and/or stromal distribution. The gene expression profiles of prostate tumors indicated prominent differences in tumor immunobiology between African-American and European-American men and portrayed a distinct difference in the tumor microenvironment between these two groups. We will further pursue this observation in a collaboration with Arthur Hurwitz (Laboratory of Molecular Immunoregulation, CCR). We will collect tumors from surgery and compare the spectrum of immune cells that are present in tumors from African-American and European-American patients. Among the differentially expressed genes were numerous interferon gamma-inducible genes but also several genes known to induce immune tolerance. These included members of the major histocompatibility (MHC) class I gene family (HLA-E, HLA-G, HLA-F) and the gene encoding indoleamine-2,3-dioxygenase (INDO). INDO is an interferon gamma-inducible enzyme and a crucial gatekeeper in the immune escape of malignancies. INDO expression has been found to contribute to tumor cell evasion from T- cell-mediated and natural killer (NK) cell-mediated cytotoxicity, and to accelerate tumor growth. Its expression in human cancers is associated with poor outcome. In collaboration with Marston Linehan (Urologic Oncology Branch, CCR) we are studying the role of INDO in prostate tumors from African-American and European-American patients. Specimens will be collected as part of an ongoing clinical study. We hypothesize that INDO is expressed at higher levels in tumors from African-American patients than European-American patients and causes the depletion of tryptophan. In support of this study and to corroborate our finding that African-American tumors have a heightened interferon gamma activity, we will also measure serum markers for interferon activity in these patients, and in the Maryland Prostate Cancer Case-Control Study. Interferon gamma is the master regulator of the Th1 response and enhances tumor immunogenicity and abrogated tumor development in mouse models. However, an interferon gamma signature has also been shown to indicate chronic inflammation, is a marker for a chronic infection, and can induce genes (e.g., INDO) that promote disease progression. Thus, interferon gamma plays a dual role in tumor biology. We will [summary truncated at 7800 characters]