Abstract
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.
Highlights
Immune checkpoint blockade using anti-PD-1 therapy (PD-1) monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment
We demonstrate that a subset of lineage negative hematopoietic stem and progenitor cells (HSCs) that express chemokine receptor type 2 (CCR2), referred to as CCR2+HSCs, have the capacity to migrate to intracranial tumors and differentiate into professional antigen-presenting cells (APCs) within the tumor microenvironment
We found that combinatorial CCR2+HSCs plus anti-PD-1 leads to increased median survival and long-term survivors in preclinical brain tumor models that are completely refractory to PD-1 treatment alone
Summary
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. We demonstrate that a subset of lineage negative (lin−) HSCs that express chemokine receptor type 2 (CCR2), referred to as CCR2+HSCs, have the capacity to migrate to intracranial tumors and differentiate into professional antigen-presenting cells (APCs) within the tumor microenvironment This leads to increased intratumor T-cell activation after treatment with either PD-1 inhibition or adoptive cellular therapy. The APCs derived from CCR2+HSCs uniquely crosspresent tumor-derived antigens to both endogenous and adoptively transferred T lymphocytes, leading to prolonged T-cell activation within brain tumors and enhanced tumor rejection These studies demonstrate a unique role for CCR2+HSCs in overcoming brain tumor resistance to PD-1 blockade and adoptive cellular therapy
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