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

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

doi:10.1016/j.cell.2023.06.020

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3333-3349.e27
Number of pages	44
Journal	Cell
Volume	186
Issue number	16
Early online date	24 Jul 2023
DOIs	https://doi.org/10.1016/j.cell.2023.06.020
Publication status	Published - 3 Aug 2023
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2023.06.020Licence: CC BY

Version of Record with a CC BY LicenceFinal published version, 15.7 MBLicence: CC BY

Cite this

Dolton, G., Rius, C., Wall, A., Szomolay, B., Bianchi, V., Galloway, S. A. E., Hasan, M. S., Morin, T., Caillaud, M. E., Thomas, H. L., Theaker, S., Tan, L. R., Fuller, A., Topley, K., Legut, M., Attaf, M., Hopkins, J. R., Behiry, E., Zabkiewicz, J., ... Sewell, A. K. (2023). Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy. Cell, 186(16), 3333-3349.e27. https://doi.org/10.1016/j.cell.2023.06.020

@article{0cb5b0f64b0d4cdabe7463a3769ad015,

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

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.",

keywords = "Antigens, Neoplasm/metabolism, Epitopes, Immunotherapy, Lymphocytes, Tumor-Infiltrating, Neoplasms/immunology, Proteomics, Receptors, Antigen, T-Cell/metabolism",

author = "Garry Dolton and Cristina Rius and Aaron Wall and Barbara Szomolay and Valentina Bianchi and Galloway, {Sarah A E} and Hasan, {Md Samiul} and Th{\'e}o Morin and Caillaud, {Marine E} and Thomas, {Hannah L} and Sarah Theaker and Tan, {Li Rong} and Anna Fuller and Katie Topley and Mateusz Legut and Meriem Attaf and Hopkins, {Jade R} and Enas Behiry and Joanna Zabkiewicz and Caroline Alvares and Angharad Lloyd and Amber Rogers and Peter Henley and Christopher Fegan and Oliver Ottmann and Stephen Man and Crowther, {Michael D} and Marco Donia and Svane, {Inge Marie} and Cole, {David K} and Brown, {Paul E} and Pierre Rizkallah and Sewell, {Andrew K.}",

year = "2023",

month = aug,

day = "3",

doi = "10.1016/j.cell.2023.06.020",

language = "English",

volume = "186",

pages = "3333--3349.e27",

journal = "Cell",

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Dolton, G, Rius, C, Wall, A, Szomolay, B, Bianchi, V, Galloway, SAE, Hasan, MS, Morin, T, Caillaud, ME, Thomas, HL, Theaker, S, Tan, LR, Fuller, A, Topley, K, Legut, M, Attaf, M, Hopkins, JR, Behiry, E, Zabkiewicz, J, Alvares, C, Lloyd, A, Rogers, A, Henley, P, Fegan, C, Ottmann, O, Man, S, Crowther, MD, Donia, M, Svane, IM, Cole, DK, Brown, PE, Rizkallah, P & Sewell, AK 2023, 'Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy', Cell, vol. 186, no. 16, pp. 3333-3349.e27. https://doi.org/10.1016/j.cell.2023.06.020

TY - JOUR

T1 - Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy

AU - Dolton, Garry

AU - Rius, Cristina

AU - Wall, Aaron

AU - Szomolay, Barbara

AU - Bianchi, Valentina

AU - Galloway, Sarah A E

AU - Hasan, Md Samiul

AU - Morin, Théo

AU - Caillaud, Marine E

AU - Thomas, Hannah L

AU - Theaker, Sarah

AU - Tan, Li Rong

AU - Fuller, Anna

AU - Topley, Katie

AU - Legut, Mateusz

AU - Attaf, Meriem

AU - Hopkins, Jade R

AU - Behiry, Enas

AU - Zabkiewicz, Joanna

AU - Alvares, Caroline

AU - Lloyd, Angharad

AU - Rogers, Amber

AU - Henley, Peter

AU - Fegan, Christopher

AU - Ottmann, Oliver

AU - Man, Stephen

AU - Crowther, Michael D

AU - Donia, Marco

AU - Svane, Inge Marie

AU - Cole, David K

AU - Brown, Paul E

AU - Rizkallah, Pierre

AU - Sewell, Andrew K.

PY - 2023/8/3

Y1 - 2023/8/3

N2 - 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.

AB - 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.

KW - Antigens, Neoplasm/metabolism

KW - Epitopes

KW - Immunotherapy

KW - Lymphocytes, Tumor-Infiltrating

KW - Neoplasms/immunology

KW - Proteomics

KW - Receptors, Antigen, T-Cell/metabolism

U2 - 10.1016/j.cell.2023.06.020

DO - 10.1016/j.cell.2023.06.020

M3 - Article

C2 - 37490916

SN - 0092-8674

VL - 186

SP - 3333-3349.e27

JO - Cell

JF - Cell

IS - 16

ER -