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

Catherine T Flores1, Tyler J Wildes2, Jeffrey A Drake2

  • 1University 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.

Nature Communications
|October 19, 2018
PubMed

Insights

Hematopoietic stem cells (HSCs) expressing C-C chemokine receptor type 2 (CCR2+) overcome resistance to immunotherapy in brain tumors. This approach sensitizes models of glioblastoma and medulloblastoma to curative treatment.

Area of Science:

  • Immunology
  • Neuro-oncology
  • Stem Cell Biology

Background:

  • Immune checkpoint blockade with anti-PD-1 antibodies shows promise for solid tumors but is ineffective against brain tumors.
  • Central nervous system (CNS) malignancies are often resistant to current immunotherapeutic strategies.

Purpose of the Study:

  • To investigate the potential of hematopoietic stem and progenitor cells (HSCs) to overcome resistance to immunotherapy in brain tumors.
  • To explore the role of C-C chemokine receptor type 2 (CCR2)-expressing HSCs in sensitizing brain tumors to PD-1 blockade and adoptive cellular therapy.

Main Methods:

  • Utilized preclinical models of glioblastoma and medulloblastoma.
  • Administered bone marrow-derived, lineage-negative HSCs expressing CCR2 (CCR2+ HSCs) in combination with PD-1 blockade.
  • Analyzed T-cell frequency, activation, and differentiation of HSCs into antigen-presenting cells within the tumor microenvironment.

Main Results:

  • CCR2+ HSC transfer reversed resistance to PD-1 blockade in CNS malignancies.
  • HSC transfer enhanced T-cell frequency and activation within intracranial tumors.
  • CCR2+ HSCs migrated to brain tumors, differentiated into antigen-presenting cells, and cross-presented tumor antigens to CD8+ T cells, sensitizing tumors to immunotherapy.

Conclusions:

  • CCR2+ HSCs represent a novel therapeutic strategy to overcome brain tumor resistance to PD-1 checkpoint blockade.
  • HSC transfer can sensitize invasive brain tumors, including glioblastoma and medulloblastoma, to both PD-1 blockade and adoptive cellular therapy.

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