| First Author | Srirat T | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 3 | Pages | 113898 |
| PubMed ID | 38451819 | Mgi Jnum | J:347110 |
| Mgi Id | MGI:7616674 | Doi | 10.1016/j.celrep.2024.113898 |
| Citation | Srirat T, et al. (2024) NR4a1/2 deletion promotes accumulation of TCF1(+) stem-like precursors of exhausted CD8(+) T cells in the tumor microenvironment. Cell Rep 43(3):113898 |
| abstractText | 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. |
