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

Garry Dolton ,Barbara Szomolay,Cristina Rius ,Joanna Zabkiewicz ,Anna Fuller ,Mateusz Legut ,Alun G Lloyd ,Enas M Behiry ,Katie Topley ,Paul E Brown ,Meriem Attaf ,Caroline Alvares ,Christopher Fegan ,Md Faruk Hasan ,Stephen Man ,Oliver G Ottmann ,Peter Henley ,Théo Morin ,Sarah A E Galloway ,David K Cole ,Jade R Hopkins ,Michael D Crowther ,Marine E Caillaud ,Li Rong Tan ,Amber Rogers ,Hannah Thomas ,Inge Marie Svane ,Sarah M Theaker ,Aaron Wall ,P.j Rizkallah ,Valentina Bianchi ,Marco Donia ,Andrew K Sewell

doi:10.1016/j.cell.2023.06.020

Garry Dolton , Barbara Szomolay + Show 31 more

Open Access

https://doi.org/10.1016/j.cell.2023.06.020

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Abstract

The Tcells 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 Tcell 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 Tcells to attack cancer in several ways simultaneously. Such "multipronged" Tcells exhibited superior recognition of cancer cells compared with conventional Tcell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.

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