Crosstalk between cytokines and tryptophan metabolism: Therapeutic potential for immune effector cell-associated neurotoxicity syndrome.

Neuromodulation by cytokine networks plays a pivotal role in maintaining central nervous system (CNS) homeostasis. Cytokine release syndrome (CRS) and neurotoxicity are frequently and concurrently observed during chimeric antigen receptor (CAR) T cell therapy, suggesting that they are intrinsically related. Immune hyperactivation occurs after CAR-T cell infusion into human body, and the excessive secretion of cytokines results in an "overspill" into the circulation, causing multiple pathophysiological disorders, such as systemic inflammation, elevated vascular permeability and metabolic disturbance. Mounting evidence has revealed that the various pathologies of CNS are accompanied by the alterations in tryptophan metabolism. Here, we will review the advances in immune effector cell-associated neurotoxicity syndrome (ICANS) during CAR-T cell therapy, with particular focus on the crosstalk between cytokines and tryptophan metabolism for the implications for ICANS. Based on the role of tryptophan metabolism in neurological disorders, we propose a model wherein acute inflammation combines to increase brain permeability, and cytokines driven-tryptophan metabolism may subsequently synergize with host cells to trigger the occurrence of ICANS. Furthermore, we discuss the potential of crosstalk between cytokines and tryptophan metabolism as therapeutic targets in clinical applications to provide insight into possible therapeutic strategies for ICANS.