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

被引：69

作者：

Dolton, Garry ^{[1
]}

Rius, Cristina ^{[1
]}

Wall, Aaron ^{[1
]}

Szomolay, Barbara ^{[2
]}

Bianchi, Valentina ^{[1
]}

Galloway, Sarah A. E. ^{[1
]}

Hasan, Md Samiul ^{[1
]}

Morin, Theo ^{[1
]}

Caillaud, Marine E. ^{[1
]}

Thomas, Hannah L. ^{[1
]}

Theaker, Sarah ^{[1
]}

Tan, Li Rong ^{[1
]}

Fuller, Anna ^{[1
]}

Topley, Katie ^{[1
]}

Legut, Mateusz ^{[1
]}

Attaf, Meriem ^{[1
]}

Hopkins, Jade R. ^{[1
]}

Behiry, Enas ^{[1
]}

Zabkiewicz, Joanna ^{[3
]}

Alvares, Caroline ^{[3
]}

Lloyd, Angharad ^{[1
]}

Rogers, Amber ^{[1
]}

Henley, Peter ^{[3
]}

Fegan, Christopher ^{[3
]}

Ottmann, Oliver ^{[3
]}

Man, Stephen ^{[3
]}

Crowther, Michael D. ^{[1
,4
]}

Donia, Marco ^{[4
]}

Svane, Inge Marie ^{[4
]}

Cole, David K. ^{[1
]}

Brown, Paul E. ^{[5
]}

Rizkallah, Pierre ^{[1
]}

Sewell, Andrew K. ^{[1
,2
]}

机构：

[1] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, Wales

[2] Wales Heart Res Inst, Cardiff CF14 4XN, Wales

[3] Cardiff Univ, Sch Med, Div Canc & Genet, Cardiff CF14 4XN, Wales

[4] Copenhagen Univ Hosp, Natl Ctr Canc Immune Therapy, Dept Oncol, Herlev, Denmark

[5] Univ Warwick, Zeeman Inst, Coventry CV4 7AL, England

来源：

CELL | 2023年 / 186卷 / 16期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

BINDING-AFFINITY; PEPTIDE; EXPRESSION; CRYSTALLIZATION; OVEREXPRESSION; REGRESSION; MELANOMA; THERAPY; GENE; RECOGNITION;

D O I：

10.1016/j.cell.2023.06.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3333 / +

页数：45

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