PMID- 28819022
OWN - NLM
STAT- MEDLINE
DCOM- 20171106
LR  - 20181015
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 77
IP  - 20
DP  - 2017 Oct 15
TI  - beta-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an
      Effector Phenotype in CD8(+) T Cells and Undermines Checkpoint Inhibitor Therapy.
PG  - 5639-5651
LID - 10.1158/0008-5472.CAN-17-0546 [doi]
AB  - The immune context of tumors has significant prognostic value and is predictive
      of responsiveness to several forms of therapy, including immunotherapy. We report
      here that CD8(+) T-cell frequency and functional orientation within the tumor
      microenvironment is regulated by beta2-adrenergic receptor (beta-AR) signaling in
      host immune cells. We used three strategies-physiologic (manipulation of ambient 
      thermal environment), pharmacologic (beta-blockers), and genetic (beta2-AR
      knockout mice) to reduce adrenergic stress signaling in two widely studied
      preclinical mouse tumor models. Reducing beta-AR signaling facilitated conversion
      of tumors to an immunologically active tumor microenvironment with increased
      intratumoral frequency of CD8(+) T cells with an effector phenotype and decreased
      expression of programmed death receptor-1 (PD-1), in addition to an elevated
      effector CD8(+) T-cell to CD4(+) regulatory T-cell ratio
      (IFNgamma(+)CD8(+):Treg). Moreover, this conversion significantly increased the
      efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of 
      adrenergic stress and norepinephrine-driven beta-AR signaling to regulate the
      immune status of the tumor microenvironment and support the strategic use of
      clinically available beta-blockers in patients to improve responses to
      immunotherapy. Cancer Res; 77(20); 5639-51. (c)2017 AACR.
CI  - (c)2017 American Association for Cancer Research.
FAU - Bucsek, Mark J
AU  - Bucsek MJ
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Qiao, Guanxi
AU  - Qiao G
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - MacDonald, Cameron R
AU  - MacDonald CR
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Giridharan, Thejaswini
AU  - Giridharan T
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Evans, Lauren
AU  - Evans L
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Niedzwecki, Brian
AU  - Niedzwecki B
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Liu, Haichao
AU  - Liu H
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Kokolus, Kathleen M
AU  - Kokolus KM
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Eng, Jason W-L
AU  - Eng JW
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Messmer, Michelle N
AU  - Messmer MN
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Attwood, Kristopher
AU  - Attwood K
AD  - Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute,
      Buffalo, New York.
FAU - Abrams, Scott I
AU  - Abrams SI
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Hylander, Bonnie L
AU  - Hylander BL
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
FAU - Repasky, Elizabeth A
AU  - Repasky EA
AD  - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
      elizabeth.repasky@roswellpark.org.
LA  - eng
GR  - P30 CA016056/CA/NCI NIH HHS/United States
GR  - R01 CA099326/CA/NCI NIH HHS/United States
GR  - R01 CA140622/CA/NCI NIH HHS/United States
GR  - T32 CA085183/CA/NCI NIH HHS/United States
GR  - R03 AG049489/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, N.I.H., Extramural
DEP - 20170817
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Adrenergic beta-2 Receptor Antagonists)
RN  - 0 (Pdcd1 protein, mouse)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Receptors, Adrenergic, beta-2)
SB  - IM
MH  - Adrenergic beta-2 Receptor Antagonists/pharmacology
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Female
MH  - Immunotherapy/*methods
MH  - Mammary Neoplasms, Experimental/*immunology/therapy
MH  - Melanoma, Experimental/*immunology/therapy
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phenotype
MH  - Programmed Cell Death 1 Receptor/antagonists & inhibitors
MH  - Random Allocation
MH  - Receptors, Adrenergic, beta-2/*immunology
MH  - Signal Transduction/immunology
MH  - Temperature
PMC - PMC5645237
MID - NIHMS900085
EDAT- 2017/08/19 06:00
MHDA- 2017/11/07 06:00
CRDT- 2017/08/19 06:00
PHST- 2017/02/24 00:00 [received]
PHST- 2017/06/27 00:00 [revised]
PHST- 2017/08/08 00:00 [accepted]
PHST- 2017/08/19 06:00 [pubmed]
PHST- 2017/11/07 06:00 [medline]
PHST- 2017/08/19 06:00 [entrez]
AID - 0008-5472.CAN-17-0546 [pii]
AID - 10.1158/0008-5472.CAN-17-0546 [doi]
PST - ppublish
SO  - Cancer Res. 2017 Oct 15;77(20):5639-5651. doi: 10.1158/0008-5472.CAN-17-0546.
      Epub 2017 Aug 17.