Immune checkpoint inhibitors amplify type 2 immune mediated repair by pro-regenerative scaffolds
Extracellular matrix (ECM) scaffolds induce type 2 immunity to promote repair. Here, we show that immune cells recruited to ECM-treated murine muscle injuries and clinical soft tissue defects express immune checkpoints. Specifically, T <sub>H</sub> 2 cells and regulatory T cells (Tregs) increase LAG3 expression, while macrophages express PDL2. TCR analysis and a triple-reporter strain for interleukin (IL)-13 and Treg fate-mapping suggest that Tregs in ECM-treated wounds transition into T <sub>H</sub> 2-like exTregs that express LAG3. Immune checkpoint inhibition (ICI) significantly stimulated type 2 immunity in ECM-treated wounds, including increased T <sub>H</sub> 2 cells, Treg transition to T <sub>H</sub> 2-like exTregs, and pro-regenerative macrophages. Moreover, ICI enhanced muscle repair and reduced fibrosis in ECM-treated wounds. Collectively, these findings show Treg/T <sub>H</sub> 2 plasticity in wound healing and introduce a novel ICI application to enhance immune-mediated regeneration.
Authors
- Fei Yu (ORCID: https://orcid.org/0000-0002-6127-8255)
- Jordan Garcia (ORCID: https://orcid.org/0000-0001-5619-5546)
- Carissa Cooney
- Hongkai Ji (ORCID: https://orcid.org/0000-0002-6480-0141)
- David R. Maestas (ORCID: https://orcid.org/0000-0002-8207-1835)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Natalie Rutkowski (ORCID: https://orcid.org/0000-0002-0931-1580)
- Alexis N. Peña (ORCID: https://orcid.org/0000-0003-1899-8625)
- Kimberly K. Coca (ORCID: https://orcid.org/0000-0001-5865-9076)
- Anna Ruta (ORCID: https://orcid.org/0000-0002-4258-1785)
- Drew M. Pardoll (ORCID: https://orcid.org/0000-0001-6215-1013)
- Joscelyn C. Mejías (ORCID: https://orcid.org/0000-0003-4397-9741)
- Damon S. Cooney (ORCID: https://orcid.org/0000-0002-2786-287X)
- Patrick J. Byrne
- Elise Gray-Gaillard
- Jennifer Ellisseeff
- Kavita Krishnan
- robdert Anders
- Maria Browne
- Aledxander Bell
- Kellie Smith
- Constance Dubois
- Katlin Stivers
- Chris Cherry
Institutions
- University of Maryland, Baltimore (US)
- Bloomberg (United States) (US)
- Cleveland Clinic (US)
- Johns Hopkins University (US)
- University of Pittsburgh (US)
- Johns Hopkins Medicine (US)
- Sidney Kimmel Cancer Center (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-03
- DOI
- https://doi.org/10.64898/2026.01.31.703034
- Citations
- 1
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 22.24
Funders
- National Science Foundation
- Johns Hopkins University
- Integra LifeSciences
- National Institutes of Health