Age-related Immune-Stromal Networks Inhibit Response to Regenerative Immunotherapies

Han, J.; Cherry, C.; Ruta, A.; Maestas, D. R.; Mejias, J. C.; Nguyen, H. H.; Fertig, E. J.; Housseau, F.; Ganguly, S.; Moore, E.; Tam, A. J.; Pardoll, D. M.; Elisseeff, J. H.

doi:10.1101/2021.08.17.456641

bioRxiv · 10.1101/2021.08.17.456641

Age-related Immune-Stromal Networks Inhibit Response to Regenerative Immunotherapies

Han, J.·Cherry, C.·Ruta, A.·Maestas, D. R.·Mejias, J. C.·Nguyen, H. H.·Fertig, E. J.·Housseau, F.·Ganguly, S.·Moore, E.·Tam, A. J.·Pardoll, D. M.·Elisseeff, J. H.

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Abstract

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and could potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, we characterized how aging induces senescence and immunological changes that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Tissue signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improved healing and restored therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.

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Han, J., Cherry, C., Ruta, A., Maestas, D. R., Mejias, J. C., Nguyen, H. H., Fertig, E. J., Housseau, F., Ganguly, S., Moore, E., Tam, A. J., Pardoll, D. M., Elisseeff, J. H.. 2021-08-18. Age-related Immune-Stromal Networks Inhibit Response to Regenerative Immunotherapies. https://doi.org/10.1101/2021.08.17.456641

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