As immunosuppressive tumor-associated myeloid cells are known drivers of glioblastoma tumor progression, Turco et al. investigated whether they could be targeted and reprogrammed by systemic delivery of the toll-like receptor TLR7 and 8 (TLR7/8) agonist R848, encapsulated in a β-cyclodextrin nanoparticle (CDNP-R848). In a syngeneic glioma model, intravenous monotherapy with CDNP-R848 prolonged survival compared to controls, and led to a proinflammatory shift in the glioma TME that was independent of T and NK cells. Radiomic imaging techniques showed CDNP-R848 targeted bloodborne macrophages that reshaped the glioma TME.
Contributed by Katherine Turner
ABSTRACT: Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a _-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.
Author Info: (1) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, German
Author Info: (1) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (2) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (3) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (4) Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. (5) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (6) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (7) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (8) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (9) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. (10) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (11) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (12) Junior Research Group Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany. (13) Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. (14) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (15) School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA. (16) School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA. (17) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. (18) Junior Research Group Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany. Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany. (19) Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. (20) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, 02114, USA. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. (21) Clinical Cooperation Unit Neurooncology, DKTK within DKFZ, Heidelberg, Germany. Department of Neurology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany. (22) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (23) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (24) Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. (25) School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA. (26) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. michael.breckwoldt@med.uni-heidelberg.de. Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. michael.breckwoldt@med.uni-heidelberg.de. (27) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. m.platten@dkfz-heidelberg.de. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. m.platten@dkfz-heidelberg.de.
