Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-22885-8
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Funding
- US National Cancer Institute [RO1 AI 37562-20, P50CA168504-06A1, R35-CA197743, R01-CA208205, U01-CA224348]
- DFCI Accelerator Award
- Tosteson Fellowship
- Cancer Center Excellence Award from Massachusetts General Hospital
- CRI Irvington Postdoctoral Fellowship
- Massachusetts General Hospital
- Agency for Science, Technology, and Research (Singapore)
- Department of Defense [W81XWH-19-1-0723]
- Pew-Stewart Scholars Program for Cancer Research
- Sloan Fellowship in Chemistry
- National Foundation for Cancer Research
- Ludwig Center at Harvard
- Jane's Trust Foundation
- Advanced Medical Research Foundation
- Aid for Cancer Research Award
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In this study, researchers found that treatment with an agonistic anti-GITR antibody converts tumor infiltrating regulatory T cells to effector cells, overcoming resistance to PD1 blockade in preclinical models of GBM.
Immune 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 (alpha GITR) 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 IFN gamma, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. alpha GITR and alpha PD1 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, alpha GITR and alpha PD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models. Glioblastomas (GBM) are frequently resistant to immune checkpoint blockade therapy. Here the authors show that treatment with an agonistic anti-GITR antibody converts tumor infiltrating regulatory T cells to effector cells, overcoming resistance to PD1 blockade in preclinical models of GBM.
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