To overcome the immunosuppressive TME in glioblastoma, Lunavat and Nieland et al. identified the cell types involved in tumor control following i.t. IL-12 therapy in mice. Single cell RNAseq, targeted cell enrichment (CD45+, CD11b+), and depletion experiments demonstrated that among lymphocytes CD8+ were key to response to IL-12 and that a CCR7+ DC subset was also activated. Both cell types expressed 4-1BB and were further activatable by 4-1BBL delivered either by the implanted tumor cells transduced with Tnsf9 (encoding 4-1BBL) or by an intracerebrally administered AAV encoding 4-1BBL and actively expressed in GFAP+ astrocytes.
Contributed by Ed Fritsch
ABSTRACT: The standard of care in high-grade gliomas has remained unchanged in the past 20 years. Efforts to replicate effective immunotherapies in non-cranial tumors have led to only modest therapeutical improvements for patients with glioma. Here, we demonstrate that intratumoral (i.t.) administration of recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8(POS) T cell accumulation and conversion into an effector-like state, resulting in a dose-dependent survival benefit in preclinical glioblastoma (GB) mouse models. This tumor-reactive CD8 T cell response is further supported by intratumoral rIL-12-sensing dendritic cells (DCs) and is accompanied by the co-stimulatory receptor 4-1BB expression in both cell types. Given that DCs and CD8(POS) T cells are functionally suppressed in the tumor microenvironments (TME) of de novo and recurrent glioma patients, we tested whether anti-tumor response at the rIL-12-inflamed tumor site could be enhanced with 4-1BBL, the ligand of 4-1BB. 4-1BBL was delivered using an adeno-associated virus (AAV) vector targeting GFAP-expressing cells and resulted in prolonged survival of rIL-1 2-treated GB-bearing mice. This study establishes that tumor antigen (Ag)-specific CD8 T cell activity can be augmented by incorporating an AAV-vector-mediated gene therapy approach, effectively enhancing anti-GB immunity in the TME.
Author Info: (1) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Biomedicine, University o
Author Info: (1) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Biomedicine, University of Bergen, 5019 Bergen, Norway. (2) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands. (3) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (4) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (5) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Institute of Medical Engineering and Sciences and Department of Chemistry, Massachusetts Institute Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institutes of Technology, Cambridge, MA 02139, USA; Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada. (6) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard Medical School, Boston, MA 02215, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard Medical School, Boston, MA 02215, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. (8) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (9) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (10) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (11) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (14) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA. (15) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands. (16) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (17) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (18) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (19) Harvard-MIT Health Sciences and Technology, Cambridge, MA 02139, USA. (20) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (21) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (22) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (23) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (24) Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: kbreyne@mgh.harvard.edu.
