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A subpopulation of cancer cells with high SIRPG expression promotes immune escape of non-small cell lung carcinoma through crosstalk with Hippo signaling

ABSTRACT: Cancer stem like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we show that signal regulatory protein gamma (SIRPG) determines a small population of lung adenocarcinoma (LUAD) cancer cells for both CSLCs properties and immune evasion. SIRPGhigh population displays CSLCs properties and transmits the immune escape signal through sustaining CD47 expression to both SIRPGhigh and SIRPGlow/- tumor cells. SIRPG bridges MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation leading to cytokine release by CSLCs, which stimulates CD47 expression in LUAD cells and consequently inhibits tumor cell phagocytosis. SIRPG promotes tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPG targeting with genetic SIRPG knockdown or a SIRPG neutralization antibody inhibits CSLC phenotypes and elicits phagocytosis that suppresses tumor growth in vivo. SIRPG is upregulated in human LUAD and its overexpression predicts poor survival outcome. Thus, SIRPGhigh cells serve as CSLCs and tumor immune checkpoint initiating cells propagating the immune escape signal to the whole cancer cell populations. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPG is engaged and reveals that targeting SIRPG represents an immune and CSLC targeting strategy for lung cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192790 | GEO | 2022/01/02

REPOSITORIES: GEO

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