PMID- 28490665
OWN - NLM
STAT- MEDLINE
DCOM- 20180220
LR  - 20220331
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 9
IP  - 389
DP  - 2017 May 10
TI  - In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway 
      in anti-PD-1 therapy.
LID - 10.1126/scitranslmed.aal3604 [doi]
LID - eaal3604
AB  - Monoclonal antibodies (mAbs) targeting the immune checkpoint anti-programmed cell 
      death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment 
      of some cancers; however, these drugs are not always effective, and we still have 
      a limited understanding of the mechanisms that contribute to their efficacy or 
      lack thereof. We used in vivo imaging to uncover the fate and activity of aPD-1 
      mAbs in real time and at subcellular resolution in mice. We show that aPD-1 mAbs 
      effectively bind PD-1(+) tumor-infiltrating CD8(+) T cells at early time points 
      after administration. However, this engagement is transient, and aPD-1 mAbs are 
      captured within minutes from the T cell surface by PD-1(-) tumor-associated 
      macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both 
      on the drug's Fc domain glycan and on Fcgamma receptors (FcgammaRs) expressed by host 
      myeloid cells and extend these findings to the human setting. Finally, we 
      demonstrate that in vivo blockade of FcgammaRs before aPD-1 mAb administration 
      substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8(+) T cells and 
      enhances immunotherapy-induced tumor regression in mice. These investigations 
      yield insight into aPD-1 target engagement in vivo and identify specific Fc/FcgammaR 
      interactions that can be modulated to improve checkpoint blockade therapy.
CI  - Copyright (c) 2017, American Association for the Advancement of Science.
FAU - Arlauckas, Sean P
AU  - Arlauckas SP
AUID- ORCID: 0000-0003-4056-8824
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
AD  - Department of Radiology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
AD  - Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, 
      Boston, MA 02115, USA.
FAU - Garris, Christopher S
AU  - Garris CS
AUID- ORCID: 0000-0002-5764-6203
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
AD  - Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
FAU - Kohler, Rainer H
AU  - Kohler RH
AUID- ORCID: 0000-0001-6269-6590
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
FAU - Kitaoka, Maya
AU  - Kitaoka M
AD  - Center for Immunology and Infectious Disease, Massachusetts General Hospital, 149 
      8th Street, Charlestown, MA 02129, USA.
FAU - Cuccarese, Michael F
AU  - Cuccarese MF
AUID- ORCID: 0000-0001-7431-9573
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
FAU - Yang, Katherine S
AU  - Yang KS
AUID- ORCID: 0000-0003-0182-950X
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
FAU - Miller, Miles A
AU  - Miller MA
AUID- ORCID: 0000-0001-7638-8898
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
AD  - Department of Radiology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
FAU - Carlson, Jonathan C
AU  - Carlson JC
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
FAU - Freeman, Gordon J
AU  - Freeman GJ
AUID- ORCID: 0000-0002-7210-5616
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115, USA.
FAU - Anthony, Robert M
AU  - Anthony RM
AD  - Center for Immunology and Infectious Disease, Massachusetts General Hospital, 149 
      8th Street, Charlestown, MA 02129, USA.
FAU - Weissleder, Ralph
AU  - Weissleder R
AUID- ORCID: 0000-0003-0828-4143
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
AD  - Department of Radiology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
AD  - Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, 
      Boston, MA 02115, USA.
FAU - Pittet, Mikael J
AU  - Pittet MJ
AUID- ORCID: 0000-0002-2060-4691
AD  - Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA. mpittet@mgh.harvard.edu.
AD  - Department of Radiology, Massachusetts General Hospital, 185 Cambridge Street, 
      CPZN 5206, Boston, MA 02114, USA.
LA  - eng
GR  - R01 CA164448/CA/NCI NIH HHS/United States
GR  - U54 CA151884/CA/NCI NIH HHS/United States
GR  - R01 AI084880/AI/NIAID NIH HHS/United States
GR  - P50 CA101942/CA/NCI NIH HHS/United States
GR  - F31 CA196035/CA/NCI NIH HHS/United States
GR  - P50 CA086355/CA/NCI NIH HHS/United States
GR  - DP2 AR068272/AR/NIAMS NIH HHS/United States
GR  - R21 CA190344/CA/NCI NIH HHS/United States
GR  - R01 CA206890/CA/NCI NIH HHS/United States
GR  - R01 HL084312/HL/NHLBI NIH HHS/United States
GR  - T32 CA079443/CA/NCI NIH HHS/United States
GR  - P30 DK043351/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Receptors, IgG)
SB  - IM
CIN - Nat Rev Cancer. 2017 Jul 23;17 (7):396-397. PMID: 28642605
CIN - Nat Rev Drug Discov. 2017 Jun 29;16(7):455. PMID: 28660900
MH  - Animals
MH  - Antibodies, Monoclonal/*immunology/therapeutic use
MH  - CD8-Positive T-Lymphocytes/metabolism
MH  - Cells, Cultured
MH  - Humans
MH  - Immunotherapy/methods
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Programmed Cell Death 1 Receptor/immunology/*metabolism
MH  - Receptors, IgG/metabolism
PMC - PMC5734617
MID - NIHMS921513
COIS- Competing interests: G.J.F. has patents and potential royalties on the PD-1 
      pathway.
EDAT- 2017/05/12 06:00
MHDA- 2018/02/21 06:00
PMCR- 2017/12/18
CRDT- 2017/05/12 06:00
PHST- 2016/10/01 00:00 [received]
PHST- 2016/11/07 00:00 [revised]
PHST- 2017/03/16 00:00 [accepted]
PHST- 2017/05/12 06:00 [entrez]
PHST- 2017/05/12 06:00 [pubmed]
PHST- 2018/02/21 06:00 [medline]
PHST- 2017/12/18 00:00 [pmc-release]
AID - 9/389/eaal3604 [pii]
AID - 10.1126/scitranslmed.aal3604 [doi]
PST - ppublish
SO  - Sci Transl Med. 2017 May 10;9(389):eaal3604. doi: 10.1126/scitranslmed.aal3604.