Human leukocyte antigen class I and II complexes presenting melanoma-associated antigens (HLA-MAA complexes)

Human leukocyte antigen (HLA) class I and II complexes presenting melanoma-associated antigens (MAAs) are the primary molecular targets for T-cell-mediated immunotherapy in melanoma. HLA class I molecules present endogenous peptides to CD8+ cytotoxic T-cells, while HLA class II molecules present exogenous peptides to CD4+ helper T-cells, facilitating a coordinated immune response (Rock et al., 2016). In melanoma, these complexes display peptides derived from differentiation antigens (e.g., gp100, MART-1), cancer-testis antigens (e.g., NY-ESO-1, MAGE-A3), and tumor-specific neoantigens (van der Bruggen et al., 1991; Sahin et al., 2020). Therapeutic strategies targeting these complexes include cancer vaccines designed to elicit a polyclonal T-cell response and TCR-bispecific engagers like tebentafusp that physically bridge T-cells to specific HLA-peptide targets (Nathan et al., 2021). A major challenge in targeting these complexes is the potential for immune escape through the downregulation of HLA expression or the loss of the specific targeted antigens (Garrido et al., 2016). Furthermore, because some MAAs are expressed in normal melanocytes, treatment can lead to on-target off-tumor toxicities such as vitiligo or uveitis (Nathan et al., 2021).

Other names

MHC-peptide complexesMelanoma-associated antigen-HLA complexesMelanoma neoantigensMAA-HLA complexesTumor antigen-MHC complexes

Stimulation of antigen-specific T-cell responses via vaccination or direct T-cell redirection using bispecific molecules or TCR-engineered cells (Nathan et al., 2021; Sahin et al., 2020).