Immune checkpoint inhibitors amplify type 2 immune mediated repair bypro-regenerative scaffolds

Garcia, J.; Ruta, A.; Yu, F.; Mejias, J.; Pena, A.; Rutkowski, N.; Gray-Gaillard, E.; Dubois, C.; Cherry, C.; Browne, M.; Stivers, K.; Maestas, D.; Krishnan, K.; Bell, A.; Fertig, E. J.; Cooney, C.; Cooney, D.; Byrne, P.; Hillel, A.; Smith, K.; Ji, H.; Anders, r.; Pardoll, D.; Ellisseeff, J.

doi:10.64898/2026.01.31.703034

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bioRxiv · 10.64898/2026.01.31.703034

Immune checkpoint inhibitors amplify type 2 immune mediated repair bypro-regenerative scaffolds

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Abstract

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, TH2 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 TH2-like exTregs that express LAG3. Immune checkpoint inhibition (ICI) significantly stimulated type 2 immunity in ECM-treated wounds, including increased TH2 cells, Treg transition to TH2-like exTregs, and pro-regenerative macrophages. Moreover, ICI enhanced muscle repair and reduced fibrosis in ECM-treated wounds. Collectively, these findings show Treg/TH2 plasticity in wound healing and introduce a novel ICI application to enhance immune-mediated regeneration.

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Garcia, J., Ruta, A., Yu, F., Mejias, J., Pena, A., Rutkowski, N., Gray-Gaillard, E., Dubois, C., Cherry, C., Browne, M., Stivers, K., Maestas, D., Krishnan, K., Bell, A., Fertig, E. J., Cooney, C., Cooney, D., Byrne, P., Hillel, A., Smith, K., Ji, H., Anders, r., Pardoll, D., Ellisseeff, J.. 2026-02-03. Immune checkpoint inhibitors amplify type 2 immune mediated repair bypro-regenerative scaffolds. https://doi.org/10.64898/2026.01.31.703034

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