DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Cell reports. Medicine - 5(2024), 3 vom: 19. März, Seite 101469 |
| Sprache: |
Englisch |
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| Links: |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 03.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.xcrm.2024.101469 |
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| 100 | 1 | |a Kirk, Allison M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 22.03.2024 | ||
| 500 | |a Date Revised 03.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CD8 T cell | |
| 650 | 4 | |a DNAJB1-PRKACA | |
| 650 | 4 | |a T cell receptor | |
| 650 | 4 | |a TCR repertoire | |
| 650 | 4 | |a cell therapy | |
| 650 | 4 | |a fibrolamellar carcinoma | |
| 650 | 4 | |a gene fusion | |
| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a neoantigen | |
| 650 | 7 | |a Receptors, Antigen, T-Cell |2 NLM | |
| 650 | 7 | |a DNAJB1 protein, human |2 NLM | |
| 650 | 7 | |a HSP40 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a PRKACA protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.11 |2 NLM | |
| 650 | 7 | |a Cyclic AMP-Dependent Protein Kinase Catalytic Subunits |2 NLM | |
| 650 | 7 | |a EC 2.7.11.11 |2 NLM | |
| 700 | 1 | |a Crawford, Jeremy Chase |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Ching-Heng |e verfasserin |4 aut | |
| 700 | 1 | |a Guy, Cliff |e verfasserin |4 aut | |
| 700 | 1 | |a Pandey, Kirti |e verfasserin |4 aut | |
| 700 | 1 | |a Kozlik, Tanya |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Ravi K |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Shanzou |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Phuong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jin |e verfasserin |4 aut | |
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| 700 | 1 | |a Mettelman, Robert C |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, E Kaitlynn |e verfasserin |4 aut | |
| 700 | 1 | |a Pogorelyy, Mikhail V |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hyunjin |e verfasserin |4 aut | |
| 700 | 1 | |a Minervina, Anastasia A |e verfasserin |4 aut | |
| 700 | 1 | |a Awad, Walid |e verfasserin |4 aut | |
| 700 | 1 | |a Bajracharya, Resha |e verfasserin |4 aut | |
| 700 | 1 | |a White, Toni |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Donald |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Gordon, Brittney |e verfasserin |4 aut | |
| 700 | 1 | |a Morrison, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Glazer, Evan S |e verfasserin |4 aut | |
| 700 | 1 | |a Murphy, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yixing |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzpatrick, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Yarchoan, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Sethupathy, Praveen |e verfasserin |4 aut | |
| 700 | 1 | |a Croft, Nathan P |e verfasserin |4 aut | |
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| 700 | 1 | |a Zamora, Anthony E |e verfasserin |4 aut | |
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| 700 | 1 | |a Thomas, Paul G |e verfasserin |4 aut | |
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