Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas
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s41467-021-22885-8.pdf
Description
Published version
Size
3.53 MB
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Checksum (MD5)
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Author(s)
Amoozgar, Zohreh
Kloepper, Jonas
Ren, Jun
Tay, Rong En
Kazer, Samuel W
Kiner, Evgeny
Krishnan, Shanmugarajan
Posada, Jessica M
Ghosh, Mitrajit
Mamessier, Emilie
Date Issued
2021
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Amoozgar, Zohreh, Kloepper, Jonas, Ren, Jun, Tay, Rong En, Kazer, Samuel W et al. 2021. "Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas." Nature Communications, 12 (1).
Version
Final published version
Abstract
AbstractImmune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Koch Institute for Integrative Cancer Research at MIT
Ragon Institute of MGH, MIT and Harvard
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-021-22885-8
