In three murine models of anti-PD-1-resistant glioblastoma, Amoozgar et al. demonstrated that PD-1 blockade drove intratumoral CD4+ T cells to an anergic, immunosuppressive Treg phenotype. These Tregs expressed high levels of GITR. Both in vitro and in vivo, Treg engagement with agonistic anti-GITR inhibited expansion of anergic Tregs, even in the presence of anti-PD-1, and induced Tregs to convert to IFNγ+CD4+ T effectors. Combination anti-PD-1 and anti-GITR prolonged survival – an effect mediated by CD4+ T cells and enhanced by standard-of-care treatment (radiation and temozolomide). Survivors were immune to tumor rechallenge.
Contributed by Margot O’Toole
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 (_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_, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. _GITR and _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, _GITR and _PD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.