RRC ID 78420
Author Srirat T, Hayakawa T, Mise-Omata S, Nakagawara K, Ando M, Shichino S, Ito M, Yoshimura A.
Title NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment.
Journal Cell Rep
Abstract 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.
Volume 43(3)
Pages 113898
Published 2024-3-5
DOI 10.1016/j.celrep.2024.113898
PII S2211-1247(24)00226-2
PMID 38451819
Human and Animal Cells B16 melanoma(RCB1283)
Mice RBRC00144