Tumor-specific antigen and tumor-associated antigen presented via MHC to T-cell receptor (TSA/TAA-MHC complex)

Tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs) presented via the Major Histocompatibility Complex (MHC) represent a critical class of therapeutic targets that allow the immune system to detect intracellular oncogenic proteins. TSAs, or neoantigens, are derived from somatic mutations unique to tumor cells, making them highly specific targets with low risk of autoimmunity (Vigneron, 2015, Cancer Res). In contrast, TAAs include cancer-testis antigens, differentiation antigens, or overexpressed proteins that are shared between tumors and some normal tissues. These antigens are processed into short peptides and displayed by MHC Class I or II molecules for recognition by T-cell receptors (TCRs) on CD8+ or CD4+ T cells, respectively (National Cancer Institute, 2023). Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, such as Afamitresgene autoleucel, and Immune mobilizing monoclonal TCRs Against Cancer (ImmTACs) like Tebentafusp (FDA, 2022). While highly potent, these therapies require precise patient selection based on HLA-type and antigen expression. A significant challenge in targeting these complexes is the potential for lethal off-target cross-reactivity if the targeted peptide sequence is similar to one found in vital organs, as well as the ability of tumors to evade detection by downregulating MHC expression (Linette et al., 2013, Blood).

Other names

Neoantigen-MHC complexCancer-testis antigen (CTA)Oncofetal antigenDifferentiation antigenPeptide-MHC complexpMHCTumor-specific neoantigen

Drugs targeting these complexes utilize engineered T-cell receptors (TCRs) or soluble TCR-bispecific molecules to recognize specific intracellularly derived peptide fragments presented by Major Histocompatibility Complex (MHC) molecules on the tumor surface. This recognition triggers the formation of an immunological synapse, leading to T-cell activation and the release of cytotoxic molecules like perforin and granzymes, which induce apoptosis in the target cancer cell (Nathan et al., 2021, NEJM; Adaptimmune, 2024).