Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P42574 (
caspase-3
)
45,978
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cytokine release syndrome
(
CRS
) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying
CRS
remains unclear. Here, we show that tumor cell pyroptosis triggers
CRS
during CAR T cell therapy. We find that CAR T cells rapidly activate
caspase 3
in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent
CRS
. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates
CRS
occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of
CRS
. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8
+
T cells is critical for CAR T cells to induce target cell pyroptosis.
...
PMID:Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. 3195 57
