NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
T cell exhaustion impairs tumor immunity and contributes to resistance against immune checkpoint inhibitors. The nuclear receptor subfamily 4 group A (NR4a) family of nuclear receptors plays a crucial role in driving T cell exhaustion. In this study, we observe that NR4a1 and NR4a2 deficiency in CD8+ tumor-infiltrating lymphocytes (TILs) results in potent tumor eradication and exhibits not only reduced exhaustion characteristics but also an increase in the precursors/progenitors of exhausted T (Pre-Tex) cell fraction. Serial transfers of NR4a1-/-NR4a2-/-CD8+ TILs into tumor-bearing mice result in the expansion of TCF1+ (Tcf7+) stem-like Pre-Tex cells, whereas wild-type TILs are depleted upon secondary transfer. NR4a1/2-deficient CD8+ T cells express higher levels of stemness/memory-related genes and illustrate potent mitochondrial oxidative phosphorylation. Collectively, these findings suggest that inhibiting NR4a in tumors represents a potent immuno-oncotherapy strategy by increasing stem-like Pre-Tex cells and reducing exhaustion of CD8+ T cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Cell reports - 43(2024), 3 vom: 26. März, Seite 113898 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Srirat, Tanakorn [VerfasserIn] |
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| Links: |
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| Themen: |
CP: Cancer |
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| Anmerkungen: |
Date Completed 01.04.2024 Date Revised 03.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2024.113898 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369415744 |
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| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a T cell exhaustion impairs tumor immunity and contributes to resistance against immune checkpoint inhibitors. The nuclear receptor subfamily 4 group A (NR4a) family of nuclear receptors plays a crucial role in driving T cell exhaustion. In this study, we observe that NR4a1 and NR4a2 deficiency in CD8+ tumor-infiltrating lymphocytes (TILs) results in potent tumor eradication and exhibits not only reduced exhaustion characteristics but also an increase in the precursors/progenitors of exhausted T (Pre-Tex) cell fraction. Serial transfers of NR4a1-/-NR4a2-/-CD8+ TILs into tumor-bearing mice result in the expansion of TCF1+ (Tcf7+) stem-like Pre-Tex cells, whereas wild-type TILs are depleted upon secondary transfer. NR4a1/2-deficient CD8+ T cells express higher levels of stemness/memory-related genes and illustrate potent mitochondrial oxidative phosphorylation. Collectively, these findings suggest that inhibiting NR4a in tumors represents a potent immuno-oncotherapy strategy by increasing stem-like Pre-Tex cells and reducing exhaustion of CD8+ T cells | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a CP: Immunology | |
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| 700 | 1 | |a Mise-Omata, Setsuko |e verfasserin |4 aut | |
| 700 | 1 | |a Nakagawara, Kensuke |e verfasserin |4 aut | |
| 700 | 1 | |a Ando, Makoto |e verfasserin |4 aut | |
| 700 | 1 | |a Shichino, Shigeyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Minako |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshimura, Akihiko |e verfasserin |4 aut | |
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