Specific human leukocyte antigen class i genotypes predict prognosis in resected pancreatic adenocarcinoma: A retrospective cohort study

Abstract

Background: Patients with resected pancreatic adenocarcinoma (PAAD) often experience short-term relapse and dismal survival, suggesting an urgent need to develop predictive and/or prognostic biomarkers for these populations. Given the potential associations of the human leukocyte antigen class I (HLA-I) genotype with oncogenic mutational profile and immunotherapy efficacy, we aimed to assess whether differential HLA-I genotype could predict the postoperative outcomes in resected PAAD patients. Materials and Methods: HLA-I (A, B, and C) genotyping and somatic variants of 608 Chinese PAAD patients were determined by targeted next-generation sequencing of matched blood cells and tumor tissues. HLA-A/B alleles were classified with the available definition of 12 supertypes. The Kaplan-Meier curves of disease-free survival (DFS) and multivariable Cox proportional-hazards regression analyses were performed to determine the survival difference in 226 selected patients with radical resection. Early-stage (I-II) patients constituted the majority (82%, 185/226) and some stage I-II individuals with high-quality tumor samples were analyzed by RNA-sequencing to examine immunophenotypes. Results: Patients with HLA-A02+B62+B44-had significantly shorter DFS (median, 239 vs. 410 days; hazard ratio=1.65, P=0.0189) than patients without this genotype. Notably, stage I-II patients carrying HLA-A02+B62+B44-had sharply shorter DFS than those without HLA-A02+B62+B44-(median, 237 vs. 427 days; hazard ratio=1.85, P=0.007). Multivariate analysis revealed that HLA-A02+B62+B44-was associated with significantly inferior DFS (P=0.014) in stage I-II patients but not in stage III patients. Mechanistically, HLA-A02+B62+B44-patients were associated with a high rate of KRAS G12D and TP53 mutations, lower HLA-A expression, and less inflamed T-cell infiltration. Conclusion: The current results suggest that a specific combination of germline HLA-A02/B62/B44 supertype, HLA-A02+B62+B44 -, was a potential predictor for DFS in early-stage PAAD patients after surgery.