Context and Stage-specific Effects of Nr4a in CD8 T cell Immunity 2309714

Abstract Introduction Poor CD8 T cell priming is a major barrier to immune control in microsatellite-stable (MSS) colorectal cancer (CRC), resulting in dysfunctional T cells that fail to respond to immune checkpoint blockade (ICB). Nr4a transcription factors are associated with both exhaustion and memory formation–an unresolved paradox with direct relevance to immunotherapy. Methods We used an organoid-derived MSS CRC model with tunable neoantigen expression to compare weak versus strong CD8 T cell priming. Conditional Nr4a1 deletion in CD8 T cells was used to examine early and late responses under both priming conditions, as well as tumor control and survival. Nr4a1 deletion was combined with intradermal (ID) or oral Listeria monocytogenes (Lm-Ova) neoantigen vaccination to evaluate effects on central and tissue-resident memory. Results Weak neoantigen priming rapidly induced CD8 T cell dysfunction accompanied by Nr4a upregulation, whereas strong priming elicited robust effector responses, revealing a priming strength-dependent role of Nr4a. Nr4a1 deletion enhanced early effector responses under both priming conditions but markedly increased tissue-resident memory formation only under weak priming, consistent with a priming context— and T cell stage—specific function of Nr4a1. This contrasts with prior reports that Nr4a1 is important for the development of resident memory T cells. Nr4a1 deletion led to enhanced survival in MSS CRC. Combining Nr4a1 deletion with ID or Lm-Ova vaccination enhanced central and tissue-resident memory, demonstrating that Nr4a1 is dispensable for robust memory formation under certain priming contexts. Conclusion These findings identify a targetable pathway to overcome early CD8 T cell dysfunction induced by suboptimal priming and establish Nr4a1 as a molecular rheostat linking priming strength and T cell fate to immune outcomes. Nr4a1 modulation–particularly in combination with vaccination–offers a promising strategy to enhance antitumor immunity in MSS CRC and other ICB-resistant cancers. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)