Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia
Stefanie R. Bailey, Marcela V. Maus
Stefanie R. Bailey, Marcela V. Maus
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Commentary

Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet, severe inflammatory toxicities continue to limit its broader use. In this issue of the JCI, Goala et al. uncovered a mechanistic link between IFN-γ–driven inflammation and disrupted neutrophil homeostasis, revealing that cytokine release syndrome (CRS) and immune cell–associated hematologic toxicity (ICAHT) stem from a shared biological pathway. Using IL-2Ra–deficient mice and patient samples, they showed that IFN-γ suppressed IL-17A and granulocyte colony-stimulating factor (G-CSF), disrupting granulopoiesis and neutrophil survival. Strikingly, IFN-γ blockade eased both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a path toward safer, better-tolerated cell therapies.

Authors

Stefanie R. Bailey, Marcela V. Maus

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Figure 1

IFN-γ regulates the IL-17A/G-CSF axis to drive CRS and neutropenia.

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IFN-γ regulates the IL-17A/G-CSF axis to drive CRS and neutropenia. (A) ...
(A) Goala et al. (4) report that, during CAR-T therapy, IFN-γ and TNF-α released by activated CAR-T cells promoted M1-like macrophage polarization and secretion of IL-6 and IL-12, amplifying Th1 differentiation and systemic inflammation characteristic of cytokine release syndrome (CRS). Elevated IFN-γ suppressed Th17 differentiation and reduced IL-17A production, impairing IL-17A–dependent G-CSF release from bone marrow stromal cells. The resulting decrease in G-CSF diminished granulocyte progenitor proliferation, increased neutrophil apoptosis, and caused neutropenia. (B) Genetic deletion or blockade of IFN-γ restored Th17 differentiation and IL-17A/G-CSF signaling, normalizing granulopoiesis and mitigating neutropenia without compromising CAR-T efficacy. These findings reveal IFN-γ as a mechanistic bridge between systemic cytokine release and bone marrow suppression, suggesting that IFN-γ modulation may improve the safety of CAR-T cell therapy.