Spatial Transcriptomics on a Diverse Pancreatic Cancer Cohort Reveals Race-Related Differences in Tumor Subtypes and Immune Microenvironments

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 analysis of tumor subtypes and cellular microenvironments in a diverse PDAC cohort could help provide insights into cell and molecular differences in BAA cancer cells. Here, we conducted a multi-omics interrogation of BAA versus NAA PDAC using whole exome sequencing, spatial transcriptomics (ST), and spatial proteomics. Whole exome sequencing confirmed patient ancestry and showed no significant differences in driver mutations between race groups. 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. Analysis of tertiary lymphoid structures in a validation cohort revealed that tumors in BAA patients displayed larger TLS size and number compared to NAA. In conclusion, these findings identify an increased intermediate molecular subtype signature in BAA tumors at the expense of cells with a classical subtype, accompanied by a distinct immune cell composition and spatial distribution. This study highlights that health disparities in patients of different ancestries may have a molecular basis that influences tumor aggressiveness and the immune response, which may inform therapeutic strategies.