PMID- 37844448
OWN - NLM
STAT- MEDLINE
DCOM- 20231103
LR  - 20231105
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 682
DP  - 2023 Nov 19
TI  - SIRP-alpha-IL-6 axis induces immunosuppressive macrophages in non-small-cell lung 
      cancer.
PG  - 386-396
LID - S0006-291X(23)01187-7 [pii]
LID - 10.1016/j.bbrc.2023.10.035 [doi]
AB  - Signal regulatory protein-alpha (SIRPalpha) and IL-6 participate in the induction of 
      tumor immune suppressive environment and facilitate tumor growth. In this study, 
      we found that SIRPalpha was significantly elevated in macrophages of non-small cell 
      lung cancer (NSCLC) tissues, which was positively correlated to the expression of 
      CD163, PD-1, IL-6, and lung cancer progression. SIRPalpha in peripheral blood 
      mononuclear cells (PBMCs) of NSCLC patients was also associated with CD163, PD-1, 
      and plasma IL-6. Blockade of SIRPalpha signaling in SIRPalpha (+/-) and SIRPalpha(-/-) mice 
      attenuated lung cancer growth and reduced IL-6 expression in LLC 
      cells-transplanted murine lung cancer model. Co-targeting SIRPalpha and IL-6 
      additively suppressed the expression of IL-6 and activation of STAT3, accompanied 
      with a reduced population of pro-tumorigenic CD206(+) M2 subtype of macrophages, 
      PD-1(+) tumor-associated macrophages (TAMs), and PD-1(+)CD8(+) T cells in tumor 
      tissues of anti-IL-6 antibody (aIL-6)-treated mice deficient in SIRPalpha. Further in 
      vitro studies showed that blockade of SIRPalpha signaling by anti-SIRPalpha effectively 
      improved phagocytosis of human PBMCs. IL-6 treatment improved polarization of M2 
      subtypes and the expression of PD-1 in bone marrow-derived macrophages (BMDMs); 
      whereas both aIL-6 and STAT3 inhibitor C188-9 suppressed the expression of PD-1 
      and SIRPalpha in BMDMs. M2 cell-biased polarization was also reduced in aIL-6 or 
      C188-9 treated BMDMs. Thereby, SIRPalpha and IL-6 form a positive feedback loop and 
      regulate each other through STAT3 signaling in macrophages. The increased 
      SIRPalpha/IL-6 axis may promote immune suppressive environment and lung cancer 
      growth, which may be a potential target for clinical treatment.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Wang, Bin
AU  - Wang B
AD  - Cancer Center, Department of Thoracic Surgery, Zhejiang Provincial People's 
      Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 
      Zhejiang, China; Department of Thoracic Surgery, Huadong Hospital, Fudan 
      University, Shanghai, China.
FAU - Pan, Linyue
AU  - Pan L
AD  - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 
      China.
FAU - Chen, Mengjie
AU  - Chen M
AD  - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 
      China.
FAU - Ma, Yuan
AU  - Ma Y
AD  - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 
      China.
FAU - Gao, Jiameng
AU  - Gao J
AD  - Department of Pulmonary Medicine, Minhang Hospital, Fudan University, Shanghai, 
      China.
FAU - Tang, Dongfang
AU  - Tang D
AD  - Department of Thoracic Surgery, Huadong Hospital, Fudan University, Shanghai, 
      China.
FAU - Jiang, Zhilong
AU  - Jiang Z
AD  - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 
      China. Electronic address: jiang.zhilong@zs-hospital.sh.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231010
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Interleukin-6)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (interleukin-6, mouse)
RN  - 0 (IL6 protein, human)
RN  - 0 (SIRPA protein, human)
RN  - 0 (Ptpns1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Carcinoma, Non-Small-Cell Lung/pathology
MH  - CD8-Positive T-Lymphocytes/metabolism
MH  - Interleukin-6/metabolism
MH  - Leukocytes, Mononuclear/metabolism
MH  - *Lung Neoplasms/pathology
MH  - Macrophages/metabolism
MH  - Programmed Cell Death 1 Receptor/metabolism
OTO - NOTNLM
OT  - IL-6
OT  - Macrophages
OT  - Non-small-cell lung cancer (NSCLC)
OT  - PD-1
OT  - SIRPalpha
COIS- Declaration of competing interest The authors declare no competing interests.
EDAT- 2023/10/17 00:42
MHDA- 2023/11/01 12:43
CRDT- 2023/10/16 18:06
PHST- 2023/06/17 00:00 [received]
PHST- 2023/09/28 00:00 [revised]
PHST- 2023/10/09 00:00 [accepted]
PHST- 2023/11/01 12:43 [medline]
PHST- 2023/10/17 00:42 [pubmed]
PHST- 2023/10/16 18:06 [entrez]
AID - S0006-291X(23)01187-7 [pii]
AID - 10.1016/j.bbrc.2023.10.035 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2023 Nov 19;682:386-396. doi: 
      10.1016/j.bbrc.2023.10.035. Epub 2023 Oct 10.