IFN-γ 驱动的向 Th1 而非 Th17 分化偏移是 CAR-T 治疗中细胞因子释放综合征和中性粒细胞减少的基础

Chimeric antigen receptor T cell (CAR-T) therapy has led to significant improvements in patient survival.

However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematological toxicity (ICAHT).

We utilized IL-2Ra knockout mice to model toxicities with elevated levels of IL-6, IFN- , and TNF- and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils.

Both nontumor-bearing and Em-ALL tumor-bearing mice recapitulated the cooccurrence of CRS and neutropenia. IFN- -blockade alleviated CRS and neutropenia without affecting CAR-T efficacy.

Mechanistically, a Th1-Th17 imbalance was observed to drive cooccurrence of CRS and neutropenia in an IFN- -dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN- -to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia.

We have uncovered a biological basis for ICAHT and provide support for the use of IFN- blockade to reduce both CRS and neutropenia.