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


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.

SUBMITTER: Flores CT 

PROVIDER: S-EPMC6192988 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Lin<sup>-</sup>CCR2<sup>+</sup> hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade.

Flores Catherine T CT   Wildes Tyler J TJ   Drake Jeffrey A JA   Moore Ginger L GL   Dean Bayli DiVita BD   Abraham Rebecca S RS   Mitchell Duane A DA  

Nature communications 20181017 1


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<sup>+</sup>) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC  ...[more]

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