Related Experiment Video
Updated: Mar 8, 2026
Studying Interactions between Myeloid Cells and CAR T Cells In Vitro and In Vivo
Published on: July 25, 2025
Intrinsic immunosuppressive features of monocytes suppress CAR-T19 through IL-1 pathway modulation in mantle cell
Kun Yun1,2,3, R Leo Sakemura1,4, Ismail Can1,2,5
1T Cell Engineering Laboratory Program, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
CD19-targeted chimeric antigen receptor T cells (CAR-T19) have shown remarkable success in B cell malignancies, but most patients relapse within 1-2 years. Here, we identified interleukin-1 (IL-1) receptor antagonist (IL-1ra) as a mediator of M2-like macrophage-derived inhibition of CAR-T19 in mantle cell lymphoma (MCL), as well as a potential target to enhance CAR-T19 efficacy. In preclinical models that recapitulated interactions between tumor, macrophages, and T cells, we demonstrated that M2-derived IL-1ra impairs IL-1 signaling and functions of CAR-T19. These findings were validated using clinical samples from the ZUMA-2 trial that led to the FDA approval of CAR-T19 in MCL. Single-cell RNA sequencing of CAR-T19 products and baseline myeloid cells indicated downregulated IL-1β production, enriched immunosuppressive phenotypes, and IL-1ra upregulation in the non-responder monocytes, as well as impaired IL-1β signaling and T cell functions in the non-responder CAR-T19 products. Furthermore, our preclinical studies of IL-1β showed enhanced CAR-T antitumor activities. Collectively, these data present a potential role for IL-1 signaling and IL-1ra in CAR-T19 failure.
Insights
Interleukin-1 receptor antagonist (IL-1ra) from M2-like macrophages inhibits chimeric antigen receptor T19 (CAR-T19) cell therapy in mantle cell lymphoma. Targeting IL-1ra may improve CAR-T19 efficacy for B cell malignancies.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Chimeric antigen receptor T19 (CAR-T19) therapy shows promise for B cell malignancies but is limited by patient relapse.
- Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma.
- Understanding mechanisms of CAR-T19 resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To identify mechanisms of CAR-T19 inhibition in mantle cell lymphoma.
- To investigate the role of interleukin-1 (IL-1) signaling and IL-1 receptor antagonist (IL-1ra) in CAR-T19 efficacy.
- To explore IL-1ra as a potential therapeutic target to enhance CAR-T19 therapy.
Main Methods:
- Preclinical models simulating tumor-macrophage-T cell interactions.
- Analysis of clinical samples from the ZUMA-2 trial.
- Single-cell RNA sequencing of CAR-T19 products and myeloid cells.
- Assessment of IL-1 signaling pathway activation and T cell function.
Main Results:
- M2-like macrophages release IL-1ra, which inhibits IL-1 signaling and CAR-T19 function.
- Clinical samples from non-responders showed upregulated IL-1ra and impaired IL-1 signaling in myeloid and CAR-T19 cells.
- Preclinical studies demonstrated that IL-1β enhances CAR-T antitumor activity.
Conclusions:
- IL-1ra produced by M2-like macrophages is a key mediator of CAR-T19 resistance in MCL.
- Dysregulated IL-1 signaling contributes to CAR-T19 failure.
- Targeting the IL-1 pathway, specifically IL-1ra, represents a promising strategy to overcome CAR-T19 resistance and improve therapeutic outcomes.
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