HLA Loss of Heterozygosity: Losing Half the Presentation Repertoire

A Subtler Escape Than Total Loss

Keeping one HLA haplotype lets the tumour cell retain some antigen presentation, avoiding the natural killer cell attack that follows complete MHC class I loss, while dropping the ability to present any neoantigen restricted to the deleted alleles.

In one lung cancer study, HLA loss of heterozygosity was present in a large fraction of tumours and was often subclonal, indicating it is an ongoing adaptation to immune pressure rather than a single early event.

Why It Is Easy to Miss

Standard copy-number tools struggle at the HLA locus because the region is so polymorphic and the sequences of the different genes are similar. Dedicated algorithms that use the patient's germline HLA type are needed to call allele-specific loss reliably.

This means HLA loss of heterozygosity can be present but unreported by a routine tumour panel.

Consequences for Neoantigen Prediction

Neoantigen prediction pipelines assume a tumour can present peptides on all of a person's HLA alleles. If one haplotype is deleted, predictions against those alleles are moot, and the tumour's true presentable repertoire is smaller than it appears.

Accounting for HLA loss improves the correlation between predicted immunogenicity and actual immune pressure, but this refinement is mostly a research technique so far.

Where It Sits in Practice

HLA loss of heterozygosity is not tested for in routine oncology, and no treatment is selected on it. Its main value is explanatory: it is one reason a tumour with a high predicted neoantigen load and visible T-cell infiltration can still evade immunity and fail a checkpoint inhibitor.

For neoantigen-directed trials it matters more, because a vaccine or T-cell product aimed at a peptide restricted to a deleted allele would be inert. Research pipelines increasingly incorporate allele-specific HLA calling for this reason, and the same information helps explain why immune pressure within a tumour is uneven.

Key Takeaways

• ·HLA loss of heterozygosity deletes one parental HLA haplotype, narrowing antigen presentation.
• ·It retains partial MHC class I, avoiding natural killer cell attack, and is often subclonal.
• ·It requires specialised detection and, when present, shrinks the tumour's real neoantigen repertoire.