Abstract 6235: Clinical and phenotypic consequences of HLA mediated antigen presentation deficiency in pancreatic adenocarcinoma at bulk and single-cell resolution

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal neoplasm of the pancreas characterized by a low survival rate and limited treatment options. Despite the success of immunotherapy in various cancer types, its efficacy in PDAC remains low. The underlying reasons for this discrepancy are not fully understood, despite PDAC exhibiting a moderate mutation burden. One possible determinant could be the loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) loci, resulting in compromised antigen presentation. In this work, we aim to identify and validate HLA LOH events in two independent cohorts to gain insights into both their prevalence and clinical and phenotypic impact on PDAC. Methods: We applied LOHHLA, a specialized pipeline to identify HLA LOH events from paired whole genome sequencing to two independent cohorts comprising over 650 patients. We contextualized these results with the paired transcriptome-wide gene expression data and immunohistochemistry stains. In addition, we developed a machine learning classifier to predict HLA LOH from transcriptomic data. We transfer this classifier to single cell RNA sequencing data to identify the impact of (subclonal) HLA LOH on the tumor microenvironment. Results: HLA LOH events occur in approximately 30% of PDAC patients, with about 50% of these deletions being focal deletions. We find evidence that focal but not non-focal LOH is a driver of immune escape. Overall, we find that HLA LOH events are early genetic alterations and observe a significant association between HLA LOH and the Basal PDAC expression subtype. In addition, we find that HLA expression is the most important determinant of lymphocyte infiltration followed by an intact HLA locus. Moreover, our transcriptomic classifier allowed us to accurately identify HLA LOH events from RNA sequencing data, which we successfully validated in an independent cohort. Finally, we applied this classifier to single cell sequencing data and identified phenotypic differences in multiple compartments of the tumor microenvironment between samples with intact HLA and HLA LOH. Conclusions: In conclusion, our study provides the most in depth characterization of the consequences of altered antigen presentation in PDAC to date. We have demonstrated that HLA LOH occurs in a substantial proportion of patients. Overall, these findings contribute to a better understanding of the immune landscape in PDAC and may have implications for the development of immunotherapeutic strategies tailored to this challenging cancer type. Citation Format: Michael J. Geuenich, Barbara Gruenwald, Grainne O'Kane, Chengxin Yu, Tan Tiak Ju, Amy Zhang, Oumaima Hamza, Gun Ho Jang, Faiyaz Notta, Steven Gallinger, Kieran R. Campbell. Clinical and phenotypic consequences of HLA mediated antigen presentation deficiency in pancreatic adenocarcinoma at bulk and single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6235.