Allele-specific HLA LOH in solid tumors: distinct patterns by tumor type and potential prognostic relevance

T-cell receptors (TCRs) recognize antigens derived from fragments of somatically expressed proteins that are degraded by the proteasome and presented by specific human leukocyte antigen (HLA) molecules. Recent therapeutic advances using the TCR as a tumor-targeting moiety have focused attention on <i>HLA</i> loss of heterozygosity (LOH) as a potential resistance mechanism. Allele-specific LOH, rather than allele-agnostic, is particularly pertinent, but rarely evaluated. Using a real-world dataset comprising 78,418 cases, we demonstrate that allele-specific LOH occurs at a relatively low frequency (<10%) across all patients with cancer. We observed a modest increase in allele-specific <i>HLA</i> LOH in cancers harboring associated neoantigen driver mutations (eg, <i>KRAS</i> or <i>TP53</i> mutations), but the overall frequency remained consistently low. Furthermore, using an orthogonal dataset, we integrated clinical outcomes with <i>HLA</i> LOH and identified distinct impacts on overall survival in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) cohorts. For instance, <i>A*02:01</i>-specific LOH was linked to worse survival in CRC (HR 0.5355, 95% CI 0.2991 to 0.9589, p=0.0094) but showed a trend toward improved survival in NSCLC (HR 1.249, 95% CI 0.7778 to 2.005). These findings underscore the relevance of allele-specific <i>HLA</i> LOH assessments and reveal nuanced differences in its clinical implications, which should be accounted for in the optimization of TCR-based immunotherapies.