PMID- 33372059
OWN - NLM
STAT- MEDLINE
DCOM- 20220112
LR  - 20220112
IS  - 1557-3125 (Electronic)
IS  - 1541-7786 (Linking)
VI  - 19
IP  - 4
DP  - 2021 Apr
TI  - ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human 
      Monocytic Myeloid-Derived Suppressor Cells.
PG  - 702-716
LID - 10.1158/1541-7786.MCR-20-0622 [doi]
AB  - Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that 
      accumulate in the tumor microenvironment (TME). MDSCs have been shown to dampen 
      antitumor immune responses and promote tumor growth; however, the mechanisms of 
      MDSC induction and their role in promoting immune suppression in cancer remain 
      poorly understood. Here, we characterized the phenotype and function of monocytic 
      MDSCs (M-MDSC) generated by coculture of human peripheral blood mononuclear cells 
      with SK-MEL-5 cancer cells in vitro. We selected the SK-MEL-5 human melanoma cell 
      line to generate M-MDSCs because these cells form subcutaneous tumors rich in 
      myeloid cells in humanized mice. M-MDSCs generated via SK-MEL-5 coculture 
      expressed low levels of human leukocyte antigen (HLA)-DR, high levels of CD33 and 
      CD11b, and suppressed both CD8(+) T-cell proliferation and IFNgamma secretion. 
      M-MDSCs also expressed higher levels of immunoglobulin-like transcript 3 (ILT3, 
      also known as LILRB4) and immunoglobulin-like transcript 4 (ILT4, also known as 
      LILRB2) on the cell surface compared with monocytes. Therefore, we investigated 
      how ILT3 targeting could modulate M-MDSC cell function. Treatment with an 
      anti-ILT3 antibody impaired the acquisition of the M-MDSC suppressor phenotype 
      and reduced the capacity of M-MDSCs to cause T-cell suppression. Finally, in 
      combination with anti-programmed cell death protein 1 (PD1), ILT3 blockade 
      enhanced T-cell activation as assessed by IFNgamma secretion. IMPLICATIONS: These 
      results suggest that ILT3 expressed on M-MDSCs has a role in inducing 
      immunosuppression in cancer and that antagonism of ILT3 may be useful to reverse 
      the immunosuppressive function of M-MDSCs and enhance the efficacy of immune 
      checkpoint inhibitors.
CI  - (c)2020 American Association for Cancer Research.
FAU - Singh, Latika
AU  - Singh L
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts. 
      latika.singh@merck.com.
FAU - Muise, Eric S
AU  - Muise ES
AUID- ORCID: 0000-0002-1238-5118
AD  - Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Bhattacharya, Anannya
AU  - Bhattacharya A
AUID- ORCID: 0000-0001-6385-4028
AD  - Immunology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Grein, Jeff
AU  - Grein J
AD  - Genetics and Pharmacogenomics, Merck & Co., Inc., South San Francisco, 
      California.
FAU - Javaid, Sarah
AU  - Javaid S
AD  - Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Stivers, Peter
AU  - Stivers P
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Zhang, Jun
AU  - Zhang J
AD  - Immunology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Qu, Yujie
AU  - Qu Y
AD  - Immunology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Joyce-Shaikh, Barbara
AU  - Joyce-Shaikh B
AD  - Discovery Oncology, Merck & Co., Inc., South San Francisco, California.
FAU - Loboda, Andrey
AU  - Loboda A
AD  - Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Zhang, Chunsheng
AU  - Zhang C
AD  - Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Meehl, Michael
AU  - Meehl M
AD  - Biologics Discovery, Merck & Co., Inc., Boston, Massachusetts.
FAU - Chiang, Derek Y
AU  - Chiang DY
AUID- ORCID: 0000-0002-1131-6065
AD  - Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts.
FAU - Ranganath, Sheila H
AU  - Ranganath SH
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Rosenzweig, Michael
AU  - Rosenzweig M
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
FAU - Brandish, Philip E
AU  - Brandish PE
AD  - Discovery Oncology, Merck & Co., Inc., Boston, Massachusetts.
LA  - eng
PT  - Journal Article
DEP - 20201228
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (LILRB4 protein, human)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Immunologic)
SB  - IM
MH  - Animals
MH  - Female
MH  - Heterografts
MH  - Humans
MH  - Melanoma/*immunology/metabolism
MH  - Membrane Glycoproteins/*immunology/metabolism
MH  - Mice
MH  - Monocytes/*immunology/metabolism
MH  - Myeloid-Derived Suppressor Cells/*immunology/metabolism
MH  - Receptors, Immunologic/*immunology/metabolism
EDAT- 2020/12/30 06:00
MHDA- 2022/01/13 06:00
CRDT- 2020/12/29 06:01
PHST- 2020/07/15 00:00 [received]
PHST- 2020/10/28 00:00 [revised]
PHST- 2020/12/17 00:00 [accepted]
PHST- 2020/12/30 06:00 [pubmed]
PHST- 2022/01/13 06:00 [medline]
PHST- 2020/12/29 06:01 [entrez]
AID - 1541-7786.MCR-20-0622 [pii]
AID - 10.1158/1541-7786.MCR-20-0622 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2021 Apr;19(4):702-716. doi: 10.1158/1541-7786.MCR-20-0622. Epub 
      2020 Dec 28.