Abstract B028: HLA loss shapes sex-specific tumor-immune interfaces and subtype identity in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is uniformly resistant to immune checkpoint blockade therapies, yet the role of impaired antigen presentation in reprogramming tumor-immune interactions remains uncharacterized due to the low purity of PDAC samples and a lack of single-cell and spatial resolution. Here, using the largest epithelium-enriched human PDAC cohort to-date with matched whole-genome, RNA, and multiplexed spatial proteomics data, alongside single-cell and spatial transcriptomics, we characterize impaired antigen presentation via loss of heterozygosity at the HLA locus (HLA-LOH) in PDAC. We find 26% of PDAC patients undergo HLA-LOH, an event occurring exclusively early in tumor development. Unexpectedly, HLA loss preferentially occurs in the poor-prognosis Basal transcriptional subtype in male but not female patients. Using spatial multi-omics we uncover pervasive sex-specific spatial reorganization of the tumor-immune interface upon HLA-LOH. Further, by classifying HLA-LOH events as focal or non-focal, we discover focal loss defines a novel immune-escaped subtype, independent of known immunoreactive PDAC subtypes. Using Houdini, a transfer learning framework we developed to map HLA loss in single cell and spatial transcriptomic datasets, we identify cryptic subclonal HLA-LOH in an additional 23% of patients associated with increased tertiary lymphoid structure presence and sex-specific remodelling of tumor lesion morphology. These findings establish biological sex as a determinant of immune escape and spatial tumor-immune architecture in PDAC and define a framework for patient stratification in future immunotherapy trials.