Lin−CCR2+ hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade

Catherine T. Flores (), Tyler J. Wildes, Jeffrey A. Drake, Ginger L. Moore, Bayli DiVita Dean, Rebecca S. Abraham and Duane A. Mitchell ()
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Catherine T. Flores: University of Florida
Tyler J. Wildes: University of Florida
Jeffrey A. Drake: University of Florida
Ginger L. Moore: University of Florida
Bayli DiVita Dean: University of Florida
Rebecca S. Abraham: University of Florida
Duane A. Mitchell: University of Florida

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06182-5

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