Journal Article

IFN-γ–driven skewing towards Th1 over Th17 differentiation underlies CRS and neutropenia in CAR-T therapy

Beatty, Nolan, Kotani, Hiroshi, Ilecki, Maxwell, Goala, Payal, Tariq, Muhammad Junaid, Savid-Frontera, Constanza, Stone, Meredith L., Massillon, Duna, Jain, Michael D., Lee, Sae Bom, McSain, Shannon, Sailer, Cooper, Zhang, Yongliang, Davila, Marco L., Cortes Gomez, Eduardo, Wang, Jianmin, Boucher, Justin C., Hamid, Showkat, Pavy, Allan

2026

Overview

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-γ, and TNF-α 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-γ-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-γ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN-γ-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-γ blockade to reduce both CRS and neutropenia.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antigens / Apoptosis / Cell Differentiation - immunology / Cell survival / Chimeric antigen receptors / Cytokine Release Syndrome - etiology / Cytokine Release Syndrome - genetics / Cytokine Release Syndrome - immunology / Cytokine Release Syndrome - pathology / Cytokine storm / Female / Granulocyte colony-stimulating factor / Helper cells / Hematology / Homeostasis / Humans / Immunotherapy, Adoptive - adverse effects / Interferon-gamma - genetics / Interferon-gamma - immunology / Interleukin 2 receptors / Leukocytes (neutrophilic) / Lymphatic system / Lymphocytes / Lymphocytes T / Macrophages / Male / Mice / Mice, Knockout / Neutropenia / Neutropenia - etiology / Neutropenia - genetics / Neutropenia - immunology / Neutropenia - pathology / Neutrophils / Neutrophils - immunology / Neutrophils - pathology / Peripheral blood / Survival analysis / Th1 Cells - immunology / Th1 Cells - pathology / Th17 Cells - immunology / Th17 Cells - pathology / Toxicity / Tumor necrosis factor-α / Tumors / γ-Interferon