Secreted tryptophanyl-tRNA synthetase levels predict severe systemic and neurological toxicities following CAR T therapy [TLR2_knockdown_monocyte_RNAseq]

While both toxicities involve aberrant myeloid activation, their shared initial drivers remain elusive. Through proteomic profiling of patient samples, we identified secreted tryptophanyl-tRNA synthetase (WRS) as a key signature of these adverse events.

Cohort analyses reveal plasma WRS as a biomarker for high-grade toxicities. Mechanistically, aggregated WRS, not the diffused form, is pathogenic under the low-sodium microenvironment. Aggregated WRS was detected in both the plasma and central nervous system under pathological conditions, and functionally validated as a potential driver of both toxicities.