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SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.

Publication ,  Journal Article
Xu, C; Jin, G; Wu, H; Cui, W; Wang, Y-H; Manne, RK; Wang, G; Zhang, W; Zhang, X; Han, F; Cai, Z; Pan, B-S; Hsu, C-C; Liu, Y; Zhang, A ...
Published in: J Clin Invest
March 1, 2022

Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.

Duke Scholars

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

March 1, 2022

Volume

132

Issue

5

Location

United States

Related Subject Headings

  • Signal Transduction
  • Lung Neoplasms
  • Immunology
  • Humans
  • Hippo Signaling Pathway
  • Cell Line, Tumor
  • CD47 Antigen
  • Adenocarcinoma of Lung
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

Citation

APA
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Xu, C., Jin, G., Wu, H., Cui, W., Wang, Y.-H., Manne, R. K., … Lin, H.-K. (2022). SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling. J Clin Invest, 132(5). https://doi.org/10.1172/JCI141797
Xu, Chuan, Guoxiang Jin, Hong Wu, Wei Cui, Yu-Hui Wang, Rajesh Kumar Manne, Guihua Wang, et al. “SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.J Clin Invest 132, no. 5 (March 1, 2022). https://doi.org/10.1172/JCI141797.
Xu C, Jin G, Wu H, Cui W, Wang Y-H, Manne RK, et al. SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling. J Clin Invest. 2022 Mar 1;132(5).
Xu, Chuan, et al. “SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.J Clin Invest, vol. 132, no. 5, Mar. 2022. Pubmed, doi:10.1172/JCI141797.
Xu C, Jin G, Wu H, Cui W, Wang Y-H, Manne RK, Wang G, Zhang W, Zhang X, Han F, Cai Z, Pan B-S, Hsu C-C, Liu Y, Zhang A, Long J, Zou H, Wang S, Ma X, Duan J, Wang B, Liu W, Lan H, Xiong Q, Xue G, Chen Z, Xu Z, Furth ME, Haigh Molina S, Lu Y, Xie D, Bian X-W, Lin H-K. SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling. J Clin Invest. 2022 Mar 1;132(5).

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

March 1, 2022

Volume

132

Issue

5

Location

United States

Related Subject Headings

  • Signal Transduction
  • Lung Neoplasms
  • Immunology
  • Humans
  • Hippo Signaling Pathway
  • Cell Line, Tumor
  • CD47 Antigen
  • Adenocarcinoma of Lung
  • 42 Health sciences
  • 32 Biomedical and clinical sciences