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.
Author Info: (1) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (2) Edwin L. Steele Labo
Author Info: (1) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (2) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (3) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School, Boston, MA, USA. (5) Department of Chemistry, Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Broad Institute of MIT and Harvard University, Cambridge, MA, USA. Ragon Institute of MGH, MIT & Harvard, Cambridge, MA, USA. Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, USA. (6) Department of Immunology, Harvard Medical School, Boston, MA, USA. (7) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (8) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (9) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (10) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (11) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (12) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (13) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (14) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (15) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (16) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (17) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (18) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (19) Department of Chemistry, Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Broad Institute of MIT and Harvard University, Cambridge, MA, USA. Ragon Institute of MGH, MIT & Harvard, Cambridge, MA, USA. Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, USA. (20) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. (21) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School, Boston, MA, USA. Jain@steele.mgh.harvard.edu. (22) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA. Hye-Jung_kim@dfci.harvard.edu.
