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

被引：51

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：

英国医学研究理事会; 英国生物技术与生命科学研究理事会;

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

共 78 条

[1] T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression
Andersen, R.
Borch, T. H.
Draghi, A.
Gokuldass, A.
Rana, M. A. H.
Pedersen, M.
Nielsen, M.
Kongsted, P.
Kjeldsen, J. W.
Westergaard, M. C. W.
Radic, H. D.
Chamberlain, C. A.
Holmich, L. R.
Hendel, H. W.
Larsen, M. S.
Met, O.
Svane, I. M.
Donia, M.
[J]. ANNALS OF ONCOLOGY, 2018, 29 (07) : 1575 - 1581
[2] Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen
Andersen, Rikke
Donia, Marco
Ellebaek, Eva
Borch, Troels Holz
Kongsted, Per
Iversen, Trine Zeeberg
Holmich, Lisbet Rosenkrantz
Hendel, Helle Westergren
Met, Ozcan
Andersen, Mads Hald
Straten, Per Thor
Svane, Inge Marie
[J]. CLINICAL CANCER RESEARCH, 2016, 22 (15) : 3734 - 3745
[3] Overexpression of IGF2 mRNA-Binding Protein 2 (IMP2/p62) as a Feature of Basal-like Breast Cancer Correlates with Short Survival
Barghash, A.
Helms, V.
Kessler, S. M.
[J]. SCANDINAVIAN JOURNAL OF IMMUNOLOGY, 2015, 82 (02) : 142 - 143
[4] Elevated expression of the IGF2 mRNA binding protein 2 (IGF2BP2/IMP2) is linked to short survival and metastasis in esophageal adenocarcinoma
Barghash, Ahmad
Golob-Schwarzl, Nicole
Helms, Volkhard
Haybaeck, Johannes
Kessler, Sonja M.
[J]. ONCOTARGET, 2016, 7 (31) : 49743 - 49750
[5] Berset M, 2001, INT J CANCER, V95, P73, DOI 10.1002/1097-0215(20010120)95:1<73::AID-IJC1013>3.3.CO
[6] 2-J
[7] MiXCR: software for comprehensive adaptive immunity profiling
Bolotin, Dmitriy A.
Poslavsky, Stanislav
Mitrophanov, Igor
Shugay, Mikhail
Mamedov, Ilgar Z.
Putintseva, Ekaterina V.
Chudakov, Dmitriy M.
[J]. NATURE METHODS, 2015, 12 (05) : 380 - 381
[8] Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma
Borch, Troels Holz
Andersen, Rikke
Ellebaek, Eva
Met, Ozcan
Donia, Marco
Marie Svane, Inge
[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2020, 8 (02)
[9] Stable, soluble T-cell receptor molecules for crystallization and therapeutics
Boulter, JM
Glick, M
Todorov, PT
Baston, E
Sami, M
Rizkallah, P
Jakobsen, BK
[J]. PROTEIN ENGINEERING, 2003, 16 (09): : 707 - 711
[10] TCR/pMHC Optimized Protein crystallization Screen
Bulek, Anna M.
Madura, Florian
Fuller, Anna
Holland, J.
Schauenburg, Andrea J. A.
Sewell, Andrew K.
Rizkallah, Pierre J.
Cole, David K.
[J]. JOURNAL OF IMMUNOLOGICAL METHODS, 2012, 382 (1-2) : 203 - 210

← 1 2 3 4 5 6 7 8 →