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HLA-A is the molecule that holds up short pieces of a cell's proteins for T cells to inspect. Engineered T-cell receptor therapies such as tebentafusp and afami-cel only work in people with the HLA-A*02 variant, because the receptor recognises the tumour peptide sitting in that particular groove.
HLA-A (chromosome 6p22.1) is a class I MHC molecule that, with beta-2-microglobulin, displays mainly viral and tumour-derived peptides for recognition by the alpha-beta T-cell receptor on HLA-A-restricted CD8 T cells, guiding the response that eliminates infected or transformed cells; it can also present self-peptides from signal sequences, to which T cells are normally inactivated (UniProt P04439). It matters in oncology because TCR-based drugs are allele-specific: tebentafusp (gp100 peptide on HLA-A*02:01, approved 2022 for uveal melanoma), afamitresgene autoleucel (MAGE-A4 230-239 peptide on HLA-A*02, approved for synovial sarcoma), letetresgene autoleucel (NY-ESO-1/LAGE-1a on HLA-A*02) and brenetafusp (PRAME on HLA-A*02:01) all require the HLA-A*02 genotype as well as antigen expression.
In plain words · HLA-A is the molecule that holds up short pieces of a cell's proteins for T cells to inspect. Engineered T-cell receptor therapies such as tebentafusp and afami-cel only work in people with the HLA-A*02 variant, because the receptor recognises the tumour peptide sitting in that particular groove.
HLA-A is the molecule that holds up short pieces of a cell's proteins for T cells to inspect. Engineered T-cell receptor therapies such as tebentafusp and afami-cel only work in people with the HLA-A*02 variant, because the receptor recognises the tumour peptide sitting in that particular groove.
The antigen-presentation pathway record describes the escape routes: tumours that lose beta-2-microglobulin or HLA stop showing peptides and become invisible to CD8 T cells and to these therapies, and the HLA genotype shapes which mutations are visible at all.
4 products aim at HLA-A: bispecific antibodies and cell therapies. Because it sits on the outside of the cell, it can be reached from the bloodstream: antibodies flag the cell, ADCs deliver a toxin, radioligands deliver radiation, and CAR-T or bispecifics bring a T cell.
Tumour-associated overexpression: 4 cell-killing or cell-finding medicines (Tebentafusp, Afamitresgene autoleucel, Letetresgene autoleucel and more) aim at the antigen, which HPA finds with no normal tissue stained high; the medicine relies on the tumour carrying more of it than the normal tissue it shares it with. HPA HLA-A: RNA low tissue specificity; no normal tissue stained high. Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Skin cancer (all types), Sarcomas (soft tissue, bone, GIST)); Open Targets associates it with 1 specific cancer type at or above 0.5 (diffuse large B-cell lymphoma). (Rule 5 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas HLA-A tissue; Human Protein Atlas HLA-A pathology; Open Targets ENSG00000206503 associations
First described 1979. Earliest sequence paper UniProt cites for the protein: Orr H.T. et al, Proc. Natl. Acad. Sci. U.S.A, 1979, "Comparison of amino acid sequences of two human histocompatibility antigens, HLA-A2 and HLA-B7: location of putative alloantigenic sites". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
The antigen-presentation pathway record describes the escape routes: tumours that lose beta-2-microglobulin or HLA stop showing peptides and become invisible to CD8 T cells and to these therapies, and the HLA genotype shapes which mutations are visible at all.
RNA: low tissue specificity, detected in many normal tissues.
No normal tissue stained high.
No cancer sample stained medium or high.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
Afamitresgene autoleucel was the first engineered T-cell receptor therapy approved for a solid tumour, synovial sarcoma.
Brenetafusp is a soluble T-cell receptor bispecific, tebentafusp's successor, that recognises a PRAME peptide on HLA-A*02:01 and drags T cells onto the tumour. A phase 3 with nivolumab in first-line melanoma is enrolling, but only patients carrying HLA-A*02:01, about half of those of European ancestry, are eligible.
Letetresgene autoleucel is a second engineered T-cell receptor therapy for sarcoma, targeting NY-ESO-1 in synovial sarcoma and myxoid/round cell liposarcoma; a BLA is expected by the end of 2026.
The first drug to improve survival in metastatic uveal melanoma, and the first TCR-based bispecific.
Query for this target: (TITLE:"HLA-A" OR ABSTRACT:"HLA-A" OR TITLE:"HLA-A*02" OR ABSTRACT:"HLA-A*02" OR TITLE:"HLA-A*02:01" OR ABSTRACT:"HLA-A*02:01" OR TITLE:"major histocompatibility complex, class I, A" OR ABSTRACT:"major histocompatibility complex, class I, A") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about HLA-A, not a curated reading list.
Shares The cancer-immunity cycle, Melanoma and the tag wave5-target.
Shares Antigen presentation & immune editing and the tag wave5-target.
Shares The cancer-immunity cycle and the tag wave5-target.
Shares The cancer-immunity cycle and the tag wave5-target.
Shares The cancer-immunity cycle and the tag wave5-target.
Shares Melanoma and the tag wave5-target.
Shares HLA-A*02:01 (HLA typing for TCR therapies), Brenetafusp, Afamitresgene autoleucel, PRAME.
Shares Letetresgene autoleucel, MAGE-A4, Afamitresgene autoleucel, TCR-T cell therapy.