Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy

Cell. 2023 Aug 3;186(16):3333-3349.e27. doi: 10.1016/j.cell.2023.06.020. Epub 2023 Jul 24.


The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.

Trial registration: NCT00937625.

Keywords: HLA class I; T cell receptor; TCR; TCR-T; TIL therapy; TILs; cancer immunotherapy; peptide-HLA; tumor-infiltrating lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm* / metabolism
  • Epitopes
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Proteomics*
  • Receptors, Antigen, T-Cell* / metabolism


  • Antigens, Neoplasm
  • Epitopes
  • Receptors, Antigen, T-Cell

Associated data