Abstract IA008: Spatial transcriptomics on a diverse pancreatic cancer cohort reveals Black African Americans display reduced classical and increased intermediate tumor subtype

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy 20% more likely to develop in Black African Americans (BAA), compared to Non-African Americans (NAA). Large-scale gene expression signatures of tumor subtypes and cellular microenvironments in a diverse PDAC cohort has not been rigorously evaluated. Here we present, for the first time, a multi-omics interrogation of BAA versus NAA PDAC using whole exome sequencing, spatial transcriptomics (ST), and spatial proteomics, cell-state and tertiary lymphoid structure (TLS) distribution validated in independent cohorts. Whole exome sequencing confirmed patient ancestry and showed no significant differences in driver mutations between race groups. For ST analysis, we examined 7 BAA and 15 NAA PDAC samples, combining our cohort (n=6 BAA, n=6 NAA) with Human Tumor Atlas Network (HTAN) (n=1 BAA, n=9 NAA) data. BAA PDAC tumors had significantly fewer classical molecular subtype cells with no change in more aggressive basal-like cells. Instead, BAA patients showed a significant enrichment of the intermediate/hybrid subtype compared to NAA patients. BAA tumors also displayed increased B cell and reduced myeloid cell interactions compared to NAA tumors. Conclusions: Our findings show BAA tumors exhibited an increased intermediate molecular subtype signature at the expense of cells with a classical subtype, accompanied by a distinct immune cell composition and spatial distribution. This study highlights health disparities in patients of different ancestry may have a molecular basis that influences tumor aggressiveness and the immune response that may inform therapeutic efficacy and options.