Comparative Genomics Reveals Distinct Immune-Oncologic Pathways in African American Men with Prostate Cancer - Beyond the Abstract

Racial disparities in prostate cancer are prevalent in the United States as African American men consistently experience a higher burden of prostate cancer incidence compared to European American men. While socioeconomic status, access to optimal care, and lifestyle factors can explain a part of these disparities, distinct molecular mechanisms and underlying biologic differences in African American men remain a major contributor to prostate cancer disparities. Advancements in research on the immune landscape of prostate cancer in European American men have lacked validation among their African American counterparts.

In this current report, our study team analyzed whole transcriptome data on over 1,200 prostate cancer samples from the Decipher Genomic Resource Information Database GRID®. The team focused on 1,260 immune specific genes to determine differences between prostate cancer tumor cells in African American and European American men. We discovered striking immune differences between the two race groups. Prostate tumors from African American men exhibit unique immune repertoire and had significant enrichment of major immune pathways including pro-inflammatory cytokines, interferon (IFN)-α,β and IFN-γ, TNFα signaling, and interleukins, as compared to European American men. Furthermore, African American prostate tumors were also genomically radiosensitive and have lower Hallmark DNA damage repair genes. Additionally, the dysregulated immune-specific genes in African American men consisted of various immunosuppressive cytokines. Our work also discovered six immune-related genes with expression levels consistently different between African American and European American men across three independent datasets included the cancer genome atlas (TCGA). One gene, IFITM3, was consistently over-expressed in African American tumors that had a significantly higher rate of biochemical recurrence following primary therapy. In addition to cancer progression, this gene also plays an important role in metastasis.

These results show that the tumor immune microenvironment of African American men manifests significant expression of immune-related genes enriched for immune-inflammatory pathways, which may uniquely impact prostate cancer progression. These pathways can contribute to and escalate the growth and spread of cancer cells. The immune biologic signatures suggest prostate cancer tumors in African American men may be more sensitive to radiotherapy and could have a better response to immunotherapy.

Our genomic analysis, the largest of its kind, revealed there are major immune pathways that are significantly elevated in African American men, which can correlate with the risk of cancer recurrence and poor outcomes. Currently, there are only two immunotherapy options for prostate cancer patients: the sipuleucel-T cell vaccine and pembrolizumab. However, not everyone responds to those therapies. Our study shows that African American men have higher overall immune content within their tumor microenvironment. We can use that information to select a therapy that better targets their tumor and therefore improve their outcome.

Written by: Kosj Yamoah, MD, PhD, Section Head, Genito-Urinary Radiation Oncology, Director, Radiation Oncology Cancer Health Disparities Research, Associate Professor, Department of Radiation Oncology & Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida

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