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

Dolton, Garry, Rius, Cristina, Wall, Aaron, Szomolay, Barbara ORCID: https://orcid.org/0000-0002-5375-5533, Bianchi, Valentina, Galloway, Sarah A.E., Hasan, MD Samiul, Morin, Theo, Caillaud, Marine, Thomas, Hannah L., Theaker, Sarah, Tan, Li Rong, Fuller, Anna, Topley, Katie, Legut, Mateusz, Attaf, Merriem, Hopkins, Jade R., Behiry, Enas, Zabkiewicz, Joanna ORCID: https://orcid.org/0000-0003-0951-3825, Alvares, Caroline ORCID: https://orcid.org/0000-0003-4391-9802, Lloyd, Angharad, Rogers, Amber, Henley, Peter, Fegan, Chris ORCID: https://orcid.org/0000-0001-9685-0621, Ottmann, Oliver ORCID: https://orcid.org/0000-0001-9559-1330, Man, Stephen ORCID: https://orcid.org/0000-0001-9103-1686, Crowther, Michael D., Donia, Marco, Svane, Inge Marie, Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Brown, Paul E., Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369 and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 2023. Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy. Cell 186 (16) , pp. 3333-3349. 10.1016/j.cell.2023.06.020

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Abstract

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 “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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0092-8674
Funders:	Wellcome Trust, BBSRC
Date of First Compliant Deposit:	17 July 2023
Date of Acceptance:	24 June 2023
Last Modified:	24 Jun 2024 01:33
URI:	https://orca.cardiff.ac.uk/id/eprint/161047

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