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Odagiu, L.

Publications and source records attributed to Odagiu, L..

2 recordsLinked to original sources

The orphan nuclear receptor NR4A3 is dispensable for resident memory CD8+ T cell generation

Different memory CD8+ T cell subsets are generated following acute responses: central, effector and resident (Trm). CD8+ Trm cells established residency at the sites of infection and provide an efficient and rapid frontline defense against re-infection. The NR4A family members (NR4A1, NR4A2 and NR4A3) of orphan nuclear receptor are transiently expressed following TCR signaling and NR4As were shown to influence CD8+ T cell response. Interestingly, Nr4a1, Nr4a2 and Nr4a3 have been reported to be transcribed by CD8+ Trm cells. In absence of NR4A1, less CD8+ Trm cells are present in the liver, lungs, small intestine intra-epithelial lymphocytes (IELs) and Peyers patches. NR4A2 was shown to play a role in the generation of small intestine IEL CD8+ Trm cells. However, evidence is still lacking for the contribution of NR4A3 during CD8+ Tm cell differentiation. In this study, we evaluated the role of NR4A3 in the differentiation and maintenance of CD8+ Trm cells. Our data demonstrate that in contrast to the other family members NR4A1 and NR4A2, NR4A3 is dispensable for the generation of CD8+ Trm cells in both epithelial and non-epithelial sites.

immunology↗

NR4A3 deficiency in CD8+ T cells improves adoptive T cell therapy of cancer

NR4A3 is a transcription factor that is rapidly induced in CD8+ T cells following antigenic recognition. We have previously shown that NR4A3 deficiency induces an early molecular program that promotes memory generation and enhances effector functions, which are two essential attributes for the success of adoptive cell therapy (ACT). Therefore, we tested the hypothesis that Nr4a3-/- CD8+ T cells would have outstanding efficacy in ACT of cancer. Our results show that ACT of melanoma-bearing mice with Nr4a3-/- effector CD8+ T cells provides a better tumor control than their wild-type counterpart. The therapeutic effect observed with Nr4a3-/- effector CD8+ T cells is even better than the one observed with ACT of Nr4a3+/+ effector CD8+ T cells in combination with anti-PD-L1 treatment. scRNA-seq analysis reveals a huge heterogeneity of tumor-infiltrating lymphocytes (TILs) states following ACT. The better tumor control observed with ACT of Nr4a3-/- CD8+ effectors without anti-PD-L1 treatment correlates with an enrichment of TILs within the clusters that are associated with the anti-PD-L1 response of wild-type TILs. Moreover, the clusters that are enriched in Nr4a3-/- TILs are the ones that are enriched for effector functions. Furthermore, Nr4a3-/- and Nr4a3+/+ effectors generate distinct progenitor populations. Pseudotime analysis suggests that these progenitors have different differentiation trajectories, which may explain why ACT with Nr4a3-/- effectors is more efficient. Therefore, modulation of NR4A3 activity may represent a new strategy to generate long-lived and highly functional T cells for ACT. One sentence summaryNR4A3 deficiency improves anti-tumor CD8+ T cell response

immunology↗