PMID- 30333482
OWN - NLM
STAT- MEDLINE
DCOM- 20190109
LR  - 20210219
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 9
IP  - 1
DP  - 2018 Oct 17
TI  - Lin(-)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 
      blockade.
PG  - 4313
LID - 10.1038/s41467-018-06182-5 [doi]
LID - 4313
AB  - 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.
FAU - Flores, Catherine T
AU  - Flores CT
AUID- ORCID: 0000-0003-0973-0870
AD  - 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.
FAU - Wildes, Tyler J
AU  - Wildes TJ
AUID- ORCID: 0000-0001-8313-9144
AD  - 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.
FAU - Drake, Jeffrey A
AU  - Drake JA
AD  - 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.
FAU - Moore, Ginger L
AU  - Moore GL
AD  - 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.
FAU - Dean, Bayli DiVita
AU  - Dean BD
AD  - 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.
FAU - Abraham, Rebecca S
AU  - Abraham RS
AD  - 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.
FAU - Mitchell, Duane A
AU  - Mitchell DA
AD  - 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.
LA  - eng
GR  - R01 CA195563/CA/NCI NIH HHS/United States
GR  - UL1 TR001427/TR/NCATS NIH HHS/United States
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181017
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/immunology/*therapy
MH  - Cell Differentiation
MH  - Cell Movement
MH  - Dendritic Cells/immunology
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Glioblastoma/immunology/*therapy
MH  - *Hematopoietic Stem Cell Transplantation
MH  - *Immunotherapy, Adoptive
MH  - Lymphocyte Activation
MH  - Medulloblastoma/immunology/*therapy
MH  - Mice, Transgenic
MH  - T-Lymphocytes/physiology
PMC - PMC6192988
COIS- C.T.F. and D.A.M. hold patents related to the content of this manuscript and are 
      co-founders and equity holders in iOncologi, Inc., and as such may benefit 
      financially as a result of the outcomes of their research or work reported in 
      this publication. The remaining authors declare no competing interests.
EDAT- 2018/10/20 06:00
MHDA- 2019/01/10 06:00
PMCR- 2018/10/17
CRDT- 2018/10/19 06:00
PHST- 2017/09/22 00:00 [received]
PHST- 2018/07/26 00:00 [accepted]
PHST- 2018/10/19 06:00 [entrez]
PHST- 2018/10/20 06:00 [pubmed]
PHST- 2019/01/10 06:00 [medline]
PHST- 2018/10/17 00:00 [pmc-release]
AID - 10.1038/s41467-018-06182-5 [pii]
AID - 6182 [pii]
AID - 10.1038/s41467-018-06182-5 [doi]
PST - epublish
SO  - Nat Commun. 2018 Oct 17;9(1):4313. doi: 10.1038/s41467-018-06182-5.