{"doi":"10.1101/2025.03.06.641668","title":"The Th1/Th17 axis regulates chimeric antigen receptor (CAR) T cell therapy toxicities","abstract":"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 hematologic toxicity (ICAHT). We utilized IL-2Rα knockout mice to model cytokine 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 CRS and neutropenia. Statement of Significance Despite clinical success of CAR-T therapy, patients develop toxicities such as cytokine release syndrome and neutropenia, whose co-occurrence impacts their survival and quality-of-life. We recapitulate these toxicities in mice to discover their co-occurrence is driven by Th1-Th17 imbalance following CAR-T administration, which can be prevented via IFNγ blockade.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557396,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1457337,"name":"Yongliang Zhang","orcid":"0000-0002-4964-1285","position":1,"is_corresponding":false},{"id":1457626,"name":"Nolan Beatty","orcid":null,"position":2,"is_corresponding":false},{"id":1454245,"name":"Shannon McSain","orcid":null,"position":3,"is_corresponding":false},{"id":1032002,"name":"Cooper J. Sailer","orcid":"0000-0001-8055-588X","position":4,"is_corresponding":false},{"id":531958,"name":"Muhammad Junaid Tariq","orcid":"0000-0002-8495-8480","position":5,"is_corresponding":false},{"id":1454246,"name":"Showkat Hamid","orcid":null,"position":6,"is_corresponding":false},{"id":442062,"name":"Eduardo Cortes Gomez","orcid":"0000-0002-0966-6488","position":7,"is_corresponding":false},{"id":263779,"name":"Jianmin Wang","orcid":"0000-0001-7527-0409","position":8,"is_corresponding":false},{"id":732348,"name":"Justin C. Boucher","orcid":"0009-0008-8936-0470","position":9,"is_corresponding":false},{"id":792135,"name":"Constanza Savid-Frontera","orcid":"0000-0001-8614-3528","position":10,"is_corresponding":false},{"id":1208887,"name":"Sae Bom Lee","orcid":"0009-0003-5070-0208","position":11,"is_corresponding":false},{"id":1375677,"name":"Hiroshi Kotani","orcid":"0000-0002-6001-0636","position":12,"is_corresponding":false},{"id":108395,"name":"Michael D. Jain","orcid":"0000-0002-7789-1257","position":13,"is_corresponding":false},{"id":432861,"name":"Marco L. Davila","orcid":"0000-0002-6270-3065","position":14,"is_corresponding":false},{"id":1457336,"name":"Payal Goala","orcid":"0000-0002-4571-8513","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","pmid":"40093056","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}