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

Jordan T. Garcia; Anna Ruta; Fei Yu; Joscelyn C. Mejías; Alexis N. Peña; Natalie Rutkowski; Elise F. Gray-Gaillard; Constance Dubois; Christopher Cherry; Maria Browne; Katlin B. Stivers; David R. Maestas; Kavita Krishnan; Alexander T.F. Bell; Elana Judith Fertig; Carisa M M Cooney; Damon S. Cooney; Patrick J. Byrne; Alexander T. Hillel; Kellie Nicole Smith; Hongkai Ji; Robert Anders; Drew M. Pardoll; Jennifer H. Elisseeff

doi:10.64898/2026.01.31.703034

BioengineeringbioRxivFeb 3, 2026

Preprint

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

Jordan T. Garcia iD, Anna Ruta iD, Fei Yu iD, Joscelyn C. Mejías iD, Alexis N. Peña iD, Natalie Rutkowski iD, Elise F. Gray-Gaillard iD, Constance Dubois, Christopher Cherry iD, Maria Browne iD, Katlin B. Stivers iD, David R. Maestas iD, Kavita Krishnan iD, Alexander T.F. Bell iD, Elana Judith Fertig iD, Carisa M M Cooney iD, Damon S. Cooney iD, Patrick J. Byrne iD, Alexander T. Hillel iD, Kellie Nicole Smith iD, Hongkai Ji iD, Robert Anders, Drew M. Pardoll iD, Jennifer H. Elisseeff iD

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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