Extracellular cAMP as a potent immune modulator promotes T cell exhaustion in chronic lymphocytic leukemia 2306108

Abstract Introduction Cyclic adenosine monophosphate (cAMP) is a key intracellular second messenger known to regulate immune responses. However, its presence and functional impact in the extracellular compartment remain poorly understood. Methods We quantified plasm levels of cAMP in Chronic lymphocytic leukemia (CLL) patients. We also used bulk and single-cell RNA sequencing, multiplex cytokine profiling, and functional studies to evaluate immunological properties of extracellular cAMP Results We found that plasma cAMP levels are significantly elevated in CLL patients compared to healthy controls. Notably, we found a positive correlation between plasma cAMP levels with CLL Rai stage. We demonstrate that extracellular cAMP exerts broad immunomodulatory effects on multiple immune cell subsets, including T cells, natural killer cells, B cells, and monocytes. Extracellular cAMP selectively suppressed the expression of key proinflammatory cytokines, such as TNF-α and IFN-γ and activation markers in both CD4+ and CD8+ T cells. Prolonged cAMP inhibitory effects can promote T cell exhaustion as evidenced by the expansion of TIM-3, CD160, and PD-1 expressing T cells. This observation was further supported by a positive correlation between plasma cAMP and the frequency effector memory CD8+CD160+PD-1+ T cells in CLL patients. Transcriptomic analyses revealed downregulation of T cell effector genes and transcription factors critical for lineage differentiation and upregulation of T cell exhaustion score. In monocytes, extracellular cAMP induced a distinct transcriptional program characterized by reduced antigen-presenting functions but enhanced secretion of proinflammatory cytokines and neutrophil-recruiting chemokines. Conclusion Together, our findings reveal that extracellular cAMP is a potent immune regulator and potential biomarker in CLL. Understanding its mechanistic pathways may offer new therapeutic targets for restoring immune regulation in chronic conditions. Funding Source Cancer Research Institute of Northern Alberta Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)