Tumor-derived peptide–HLA class II complex (pHLA-II complex)

Tumor-derived peptide–HLA class II complexes are molecular structures consisting of an intracellularly processed tumor antigen fragment bound to a Human Leukocyte Antigen (HLA) class II molecule. While HLA class II expression is typically restricted to professional antigen-presenting cells (APCs) for CD4+ T cell activation, many cancers aberrantly express these molecules, allowing the tumor to be directly recognized by the immune system (PMID: 30104475). These complexes serve as highly specific targets for next-generation immunotherapies, including TCR-engineered T cells (TCR-T) and TCR-like antibodies, which can target the internal proteome of a cell that is otherwise inaccessible to standard antibody therapies (PMID: 32661156). By targeting these complexes, clinicians can leverage the potent helper and cytotoxic functions of CD4+ T cells against solid tumors and hematological malignancies. However, the clinical application of these targets requires precise HLA typing and antigen validation to avoid off-tumor effects on healthy HLA-II-expressing immune cells such as B cells and dendritic cells (PMID: 31515463).

Other names

Tumor-specific peptide-MHC class II complexpMHCIIMHC class II-restricted tumor antigenTumor-associated antigen-HLA-II complexHLA-II presented neoantigen

Therapeutic agents such as TCR-engineered T cells (TCR-T) or TCR-like antibodies bind specifically to the unique interface formed by the tumor-derived peptide nestled within the HLA class II binding groove. This binding triggers T cell activation and direct lysis of the target cell or facilitates antibody-dependent cellular cytotoxicity (ADCC).