PMID- 32213921
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210327
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 3
DP  - 2020 Mar 24
TI  - Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian 
      Tumor Microenvironment.
LID - 10.3390/cancers12030766 [doi]
LID - 766
AB  - In ovarian cancer, upregulation of the Wnt/beta-catenin pathway leads to 
      chemoresistance and correlates with T cell exclusion from the tumor 
      microenvironment (TME). Our objectives were to validate these findings in an 
      independent cohort of ovarian cancer subjects and determine whether inhibiting 
      the Wnt pathway in a syngeneic ovarian cancer murine model could create a more 
      T-cell-inflamed TME, which would lead to decreased tumor growth and improved 
      survival. We preformed RNA sequencing in a cohort of human high grade serous 
      ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine 
      (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with 
      established ID8 tumors, a murine ovarian cancer cell line. In order to 
      investigate the effect of decreased Wnt/beta-catenin pathway activity in the 
      dendritic cells (DCs), we injected ID8 cells in mice that lacked beta-catenin 
      specifically in DCs. Furthermore, to understand how much the effects of blocking 
      the Wnt/beta-catenin pathway are dependent on CD8(+) T cells, we injected ID8 cells 
      into mice with CD8(+) T cell depletion. We confirmed a negative correlation 
      between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand 
      production resulted in increases in T cell, macrophage and dendritic cell 
      functions, decreased tumor burden and improved survival. Reduced tumor growth was 
      found in mice that lacked beta-catenin specifically in DCs. When CD8(+) T cells were 
      depleted, CGX1321 treatment did not have the same magnitude of effect on tumor 
      growth. Our investigation confirmed an increase in Wnt activity correlated with a 
      decreased T-cell-inflamed environment; a relationship that was further supported 
      in our pre-clinical model that suggests inhibiting the Wnt/beta-catenin pathway was 
      associated with decreased tumor growth and improved survival via a partial 
      dependence on CD8(+) T cells.
FAU - Goldsberry, Whitney N
AU  - Goldsberry WN
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Meza-Perez, Selene
AU  - Meza-Perez S
AD  - Division of Immunology & Rheumatology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Londono, Angelina I
AU  - Londono AI
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Katre, Ashwini A
AU  - Katre AA
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Mott, Bryan T
AU  - Mott BT
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Roane, Brandon M
AU  - Roane BM
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Goel, Nidhi
AU  - Goel N
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Wall, Jaclyn A
AU  - Wall JA
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Cooper, Sara J
AU  - Cooper SJ
AUID- ORCID: 0000-0002-9627-0309
AD  - HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
FAU - Norian, Lyse A
AU  - Norian LA
AD  - Department of Nutrition Sciences, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
AD  - O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Randall, Troy D
AU  - Randall TD
AD  - Division of Immunology & Rheumatology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
AD  - O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Birrer, Michael J
AU  - Birrer MJ
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
AD  - O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Arend, Rebecca C
AU  - Arend RC
AD  - Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
AD  - O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
LA  - eng
GR  - P30 CA013148/CA/NCI NIH HHS/United States
GR  - R01 CA216234/CA/NCI NIH HHS/United States
GR  - R21 CA223126/NH/NIH HHS/United States
GR  - W81XWH-18-1-0231/U.S. Department of Defense/
PT  - Journal Article
DEP - 20200324
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7140065
OTO - NOTNLM
OT  - CGX1321
OT  - ID8 cells
OT  - ID8p53-/- cells
OT  - PORCN inhibitor
OT  - Wnt
OT  - Wnt inhibition
OT  - murine ovarian cancer
OT  - ovarian cancer
OT  - tumor microenvironment
COIS- Rebecca C. Arend is on the advisory board for Tesaro, Leap Therapeutics and 
      Clovis. The remaining authors declare no conflict of interest.
EDAT- 2020/03/28 06:00
MHDA- 2020/03/28 06:01
PMCR- 2020/03/24
CRDT- 2020/03/28 06:00
PHST- 2020/03/02 00:00 [received]
PHST- 2020/03/18 00:00 [revised]
PHST- 2020/03/19 00:00 [accepted]
PHST- 2020/03/28 06:00 [entrez]
PHST- 2020/03/28 06:00 [pubmed]
PHST- 2020/03/28 06:01 [medline]
PHST- 2020/03/24 00:00 [pmc-release]
AID - cancers12030766 [pii]
AID - cancers-12-00766 [pii]
AID - 10.3390/cancers12030766 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Mar 24;12(3):766. doi: 10.3390/cancers12030766.