Intrinsic immunosuppressive features of monocytes suppress CAR-T19 through IL-1 pathway modulation in mantle cell lymphoma
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.
Authors
- Elizabeth L. Siegler (ORCID: https://orcid.org/0000-0002-8336-4373)
- Sao-Mai Nguyen-Mau
- İsmail Can (ORCID: https://orcid.org/0000-0003-0569-5326)
- Carli M. Stewart (ORCID: https://orcid.org/0000-0002-2288-2230)
- Mike Mattie (ORCID: https://orcid.org/0000-0003-0868-3865)
- Jennifer M. Feigin (ORCID: https://orcid.org/0009-0000-6499-4655)
- Lionel Aurelien Kankeu Fonkoua (ORCID: https://orcid.org/0000-0001-5560-2103)
- Michael W. Ruff (ORCID: https://orcid.org/0000-0001-8513-9615)
- Simone Filosto (ORCID: https://orcid.org/0000-0002-7854-998X)
- Abdullah Saleh (ORCID: https://orcid.org/0000-0002-0934-3160)
- Olivia Sirpilla (ORCID: https://orcid.org/0000-0002-0634-407X)
- Fariborz Rakhshan Rohakhtar
- Ekene J. Ogbodo (ORCID: https://orcid.org/0009-0009-3552-0384)
- Saad S. Kenderian (ORCID: https://orcid.org/0000-0003-2767-3830)
- Mehrdad Hefazi (ORCID: https://orcid.org/0000-0001-8860-3380)
- Truc N Huynh
- Omar Gutierrez Ruiz
- James H. Girsch (ORCID: https://orcid.org/0000-0003-4592-4015)
- Brooke Kimball (ORCID: https://orcid.org/0009-0009-3308-2704)
- Claudia Manriquez Roman (ORCID: https://orcid.org/0000-0003-0082-9735)
- Vernadette Simon
- Reona Sakemura (ORCID: https://orcid.org/0000-0002-0293-5577)
- Shuwen Zhang (ORCID: https://orcid.org/0000-0002-5969-1737)
- Hong Xia (ORCID: https://orcid.org/0000-0002-1628-8120)
- Kun Yun
- Long Mai
Institutions
- Mayo Clinic (US)
- WinnMed (US)
- Mayo Clinic in Arizona (US)
- Gilead Sciences (Australia) (AU)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- Molecular Therapy Oncology
- Published
- 2025-04-19
- DOI
- https://doi.org/10.1016/j.omton.2025.200985
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- National Institutes of Health
- Kite Pharma
- Center for Individualized Medicine, Mayo Clinic