HLA-A
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.
Overview
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
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.
External identifiers
Biology
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.
- Eligibility marker (HLA-A*02) for TCR-T and soluble TCR therapies in uveal melanoma, synovial sarcoma and myxoid/round cell liposarcoma
- All nucleated cells (antigen presentation)
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.
Notes
top- Prevalence not recorded in this wave: HGNC and UniProt carry no positivity rates and no other source was consulted.
Latest papers
topQuery 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.
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