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

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 A*02:01-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 multiprongedT 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.

Automated summary

Tumor-infiltrating lymphocyte therapy can activate T cells of the immune system to target and eliminate solid cancers. Through the use of combinatorial peptide libraries and a proteomic database, the antigen specificities of persistent cancer-specific T cell receptors (TCRs) were identified after successful therapy for stage IV malignant melanoma. These TCRs were capable of targeting multiple tumor types through specific epitopes, and the atomic structures revealed the importance of a shared recognition motif. The ability of these multi-epitope targeting T cells to recognize cancer cells surpasses the recognition of individual epitopes, making them promising candidates for future immunotherapies.