In the context of anti-PD-1 or adoptive T cell therapy in mouse models of glioblastoma and medulloblastoma, Flores et al. found that concomitant i.v. delivery of bone marrow-derived, lineage-negative, CCR2+ hematopoietic stem and progenitor cells (HSCs) enhances T cell infiltration and activation, downregulates immunosuppressive pathways, and overcomes resistance to immunotherapy, enhancing survival. CCR2+ HSCs migrate into tumors and differentiate into CD11c+ APCs. In secondary lymphoid organs, HSC-derived APCs cross-present tumor antigens on MHC-I to endogenous and adoptively transferred CD8+ T cells.
Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C-C chemokine receptor type 2 (CCR2(+)) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2(+)HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8(+) T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2(+)HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.
Author Info: (1) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florid
Author Info: (1) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. catherine.flores@neurosurgery.ufl.edu. (2) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. (3) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. (4) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. (5) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. (6) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. (7) University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1149S Newell Dr, L2-100, Gainesville, FL, 32611, USA. duane.mitchell@neurosurgery.ufl.edu.
