PMID- 32075803
OWN - NLM
STAT- MEDLINE
DCOM- 20201109
LR  - 20211204
IS  - 2326-6074 (Electronic)
IS  - 2326-6066 (Linking)
VI  - 8
IP  - 4
DP  - 2020 Apr
TI  - Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing 
      ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma.
PG  - 436-450
LID - 10.1158/2326-6066.CIR-19-0507 [doi]
AB  - Cancer-associated fibroblasts (CAF) represent a functionally heterogeneous 
      population of activated fibroblasts that constitutes a major component of tumor 
      stroma. Although CAFs have been shown to promote tumor growth and mediate 
      resistance to chemotherapy, the mechanisms by which they may contribute to immune 
      suppression within the tumor microenvironment (TME) in lung squamous cell 
      carcinoma (LSCC) remain largely unexplored. Here, we identified a positive 
      correlation between CAF and monocytic myeloid cell abundances in 501 primary 
      LSCCs by mining The Cancer Genome Atlas data sets. We further validated this 
      finding in an independent cohort using imaging mass cytometry and found a 
      significant spatial interaction between CAFs and monocytic myeloid cells in the 
      TME. To delineate the interplay between CAFs and monocytic myeloid cells, we used 
      chemotaxis assays to show that LSCC patient-derived CAFs promoted recruitment of 
      CCR2(+) monocytes via CCL2, which could be reversed by CCR2 inhibition. Using a 
      three-dimensional culture system, we found that CAFs polarized monocytes to adopt 
      a myeloid-derived suppressor cell (MDSC) phenotype, characterized by robust 
      suppression of autologous CD8(+) T-cell proliferation and IFNgamma production. We 
      further demonstrated that inhibiting IDO1 and NADPH oxidases, NOX2 and NOX4, 
      restored CD8(+) T-cell proliferation by reducing reactive oxygen species (ROS) 
      generation in CAF-induced MDSCs. Taken together, our study highlights a pivotal 
      role of CAFs in regulating monocyte recruitment and differentiation and 
      demonstrated that CCR2 inhibition and ROS scavenging abrogate the CAF-MDSC axis, 
      illuminating a potential therapeutic path to reversing the CAF-mediated 
      immunosuppressive microenvironment.
CI  - (c)2020 American Association for Cancer Research.
FAU - Xiang, Handan
AU  - Xiang H
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts. 
      phil.brandish@bicycletx.com handan.xiang@merck.com.
FAU - Ramil, Carlo P
AU  - Ramil CP
AUID- ORCID: 0000-0002-1036-855X
AD  - Chemical Biology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Hai, Josephine
AU  - Hai J
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Zhang, Chunsheng
AU  - Zhang C
AD  - Informatics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Wang, Huijun
AU  - Wang H
AD  - Modeling and Informatics, Merck & Co., Inc., Kenilworth, New Jersey.
FAU - Watkins, Amanda A
AU  - Watkins AA
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Afshar, Roshi
AU  - Afshar R
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Georgiev, Peter
AU  - Georgiev P
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Sze, Marc A
AU  - Sze MA
AUID- ORCID: 0000-0002-3532-9653
AD  - Informatics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Song, Xuelei S
AU  - Song XS
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Curran, Patrick J
AU  - Curran PJ
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Cheng, Mangeng
AU  - Cheng M
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Miller, J Richard
AU  - Miller JR
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Sun, Dongyu
AU  - Sun D
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Loboda, Andrey
AU  - Loboda A
AD  - Informatics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Jia, Yanlin
AU  - Jia Y
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Moy, Lily Y
AU  - Moy LY
AD  - Pharmacology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Chi, An
AU  - Chi A
AD  - Chemical Biology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Brandish, Philip E
AU  - Brandish PE
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts. 
      phil.brandish@bicycletx.com handan.xiang@merck.com.
LA  - eng
PT  - Journal Article
DEP - 20200219
PL  - United States
TA  - Cancer Immunol Res
JT  - Cancer immunology research
JID - 101614637
RN  - 0 (CCR2 protein, human)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, CCR2)
RN  - EC 1.6.3.- (NADPH Oxidase 2)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NOX4 protein, human)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Cancer-Associated Fibroblasts/*immunology/metabolism/pathology
MH  - Carcinoma, Squamous Cell/*immunology/metabolism/pathology
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Female
MH  - Humans
MH  - Immunosuppression Therapy
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology/metabolism
MH  - Lung Neoplasms/*immunology/metabolism/pathology
MH  - Male
MH  - Middle Aged
MH  - Monocytes/*immunology
MH  - Myeloid-Derived Suppressor Cells/*immunology
MH  - NADPH Oxidase 2/immunology/metabolism
MH  - NADPH Oxidase 4/immunology/metabolism
MH  - Reactive Oxygen Species/*metabolism
MH  - Receptors, CCR2/immunology/metabolism
MH  - Signal Transduction
MH  - Tumor Microenvironment
EDAT- 2020/02/23 06:00
MHDA- 2020/11/11 06:00
CRDT- 2020/02/21 06:00
PHST- 2019/07/03 00:00 [received]
PHST- 2019/11/14 00:00 [revised]
PHST- 2020/02/13 00:00 [accepted]
PHST- 2020/02/23 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2020/02/21 06:00 [entrez]
AID - 2326-6066.CIR-19-0507 [pii]
AID - 10.1158/2326-6066.CIR-19-0507 [doi]
PST - ppublish
SO  - Cancer Immunol Res. 2020 Apr;8(4):436-450. doi: 10.1158/2326-6066.CIR-19-0507. 
      Epub 2020 Feb 19.