L-Kynurenine regulates immune response in ICIs-associated myocarditis via JAK/STAT pathway

Background

Immune checkpoint inhibitors associated drug-induced myocarditis (ICIAM) is a - myocarditis characterized by the infiltration of immune cells into cardiac. However, the mechanisms are unknown and effective drug therapies are lacking in clinical practice. This study aims to explore the relationship between plasma metabolites and the treatment of ICIAM.

Methods

Human plasma metabolites were analyzed using untargeted metabolomics for characteristic metabolites. For in vivo experiments, Male Balb/c mice were divided into six groups: PBS, L-Kynurenine, cTNI+PD-1 inhibitor (ICIs), ICIs+L-Kynurenine, ICIs+RO8191, ICIs+RO8191+L-Kynurenine. On day 21 post-modeling, echocardiography, ELISA and histopathology were employed to evaluate the therapeutic effect of L-Kynurenine. Flow cytometry was used to determine the proportion of immune cells in the heart and spleen. Bulk-RNAseq was conducted to analyze differential genes, and q-PCR, immunofluorescence and western blot were performed for validation experiments.

Results

Untargeted metabolomics verified that indoleamine 2,3 dioxygenase-1 (IDO1)-derived L-Kynurenine level was higher in the serum of ICIAM compared to non-ICIAM patients. Meanwhile, in vitro and in vivo experiments showed that L-Kynurenine exhibited a therapeutic ability in ICIAM by inhibiting the pro-inflammatory polarization of immune cells and the secretion of pro-inflammatory cytokines. Mechanistically, L-Kynurenine improved cardiac functions majorly by the inhibition of the JAK1/STAT3 signaling pathway.

Conclusion

L-Kynurenine exhibits significant therapeutic potential in ICIAM. The multi-roles of L-Kynurenine in regulating immune responses make it possible to be used as a targeted drug for ICIAM therapy.