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

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.

Multifunctional Nanopolymers for Blood–Brain Barrier Delivery and Inhibition of Glioblastoma Growth through EGFR/EGFRvIII, c-Myc, and PD-1

“…The molecular therapy by activating glucocorticoidinduced TNFR-related receptor (GITR) in Treg cells reprograms them in order to reduce the resistance of immune checkpoint Treg cells to immunotherapy. When the activation of GITR was combined with the αPD-1 checkpoint inhibitor, the survival of glioma-bearing mice was significantly longer in comparison with monotherapy [56].…”

Neurosurgery at the crossroads of immunology and nanotechnology. New reality in the COVID-19 pandemic

“…Another variant of lipid-based NPs is commonly called lipid nanoparticles (LNPs). They are similar in structure to liposomes and frequently utilized for nucleic acids delivery [173] . ( Fig.…”

“… May retain unwanted reactivity after synthesis resulting from non-cross-linked small molecules 4. Nanopolymers [4] , [7] , [173] , [216] , [217] , [218] Solid natural or synthetic biocompatible nanopolymers Size: 10 – 100 nm Easy manipulation of chemistry for diagnostic and treatment (theranostic) needs, with various materials and functions. Biodegradability makes them useful as drug delivery vehicles, scaffolds etc.…”

“…Lipidic Nanoparticles Big size might be problematic for BBB delivery Potential toxicity 1. Liposomes [4] , [7] , [173] , [216] , [217] , [218] Bilayered lipid or phospholipid vesicles with aqueous core 2. Unilamellar or multilamellar Size: 20 – 500 nm Biocompatible and biodegradable; this makes them attractive carriers for hydrophilic and lipophilic drugs.…”

“…These properties enable clinical use Rapid uptake by the reticuloendothelial system; low solubility and short half-life; may undergo oxidation and hydrolysis; may leak drug molecules 2. Solid lipid NPs [4] , [7] , [173] , [216] , [217] , [218] , [219] Lipid NPs (LNPs) are liposome-like structures for nucleic acids delivery. They are colloidal carriers composed of physiological lipid, dispersed in water or in an aqueous surfactant Size: 40 – 1000 nm Targeted drug delivery and good physical stability Insufficient loading capacity Drug may get expulsed during storage upon polymeric transition 3.…”