Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas

Zohreh Amoozgar, Jonas Kloepper, Jun Ren, Rong En Tay, Samuel W. Kazer, Evgeny Kiner, Shanmugarajan Krishnan, Jessica M. Posada, Mitrajit Ghosh, Emilie Mamessier, Christina Wong, Gino B. Ferraro, Ana Batista, Nancy Wang, Mark Badeaux, Sylvie Roberge, Lei Xu, Peigen Huang, Alex K. Shalek, Dai Fukumura, Hye-Jung Kim () and Rakesh K. Jain ()
Additional contact information
Zohreh Amoozgar: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Jonas Kloepper: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Jun Ren: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Rong En Tay: Dana-Farber Cancer Institute (DFCI) and Harvard Medical School
Samuel W. Kazer: Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Evgeny Kiner: Harvard Medical School
Shanmugarajan Krishnan: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Jessica M. Posada: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Mitrajit Ghosh: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Emilie Mamessier: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Christina Wong: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Gino B. Ferraro: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Ana Batista: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Nancy Wang: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Mark Badeaux: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Sylvie Roberge: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Lei Xu: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Peigen Huang: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Alex K. Shalek: Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Dai Fukumura: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)
Hye-Jung Kim: Dana-Farber Cancer Institute (DFCI) and Harvard Medical School
Rakesh K. Jain: Massachusetts General Hospital (MGH) and Harvard Medical School (HMS)

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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 (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.

Date: 2021
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DOI: 10.1038/s41467-021-22885-8

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