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ResearchIn-Press PreviewHematologyImmunologyOncology Open Access | 10.1172/JCI194631

IFNγ-driven skewing towards Th1 over Th17 differentiationunderlies CRSand neutropenia in CAR-T therapy

Payal Goala,1 Yongliang Zhang,2 Nolan J. Beatty,3 Allan Pavy,4 Shannon L. McSain,1 Cooper J. Sailer,1 Muhammad Junaid Tariq,4 Showkat Hamid,4 Eduardo Cortes Gomez,5 Jianmin Wang,5 Duna Massillon,1 Maxwell Ilecki,4 Justin C. Boucher,3 Constanza Savid-Frontera,3 Sae Bom Lee,6 Hiroshi Kotani,7 Meredith L. Stone,4 Michael D. Jain,8 and Marco L. Davila1

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Goala, P. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Zhang, Y. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Beatty, N. in: PubMed | Google Scholar |

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Pavy, A. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by McSain, S. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Sailer, C. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Tariq, M. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Hamid, S. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Cortes Gomez, E. in: PubMed | Google Scholar |

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Wang, J. in: PubMed | Google Scholar |

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Massillon, D. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Ilecki, M. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Boucher, J. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Savid-Frontera, C. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Lee, S. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Kotani, H. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Stone, M. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Jain, M. in: PubMed | Google Scholar

1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

2Iovance Biotherapeutics, San Carlos, United States of America

3Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Cancer Biology PhD Program, University of South Florida, Tampa, United States of America

7Division of Innovative Cancer Control Research, Cancer Research Institute of Kanazawa University, Kanazawa, Japan

8Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States of America

Find articles by Davila, M. in: PubMed | Google Scholar

Published October 30, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI194631.
Copyright © 2025, Goala et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 30, 2025 - Version history
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Abstract

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-2Rα knockout mice to model toxicities with elevated levels of IL6, IFNγ, and TNFα 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 non-tumor-bearing and Eμ-ALL tumor-bearing mice recapitulated the co-occurrence of CRS and neutropenia. IFNγ-blockade alleviated CRS and neutropenia without affecting CAR-T efficacy. Mechanistically, a Th1-Th17 imbalance was observed to drive co-occurrence of CRS and neutropenia in an IFNγ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFNγ-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 IFNγ-blockade to reduce both CRS and neutropenia.

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