SIRP gamma-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling

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 gamma (SIRP gamma) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRP gamma(hi) population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRP gamma(hi) and SIRP gamma(lo/-) tumor cells. SIRP gamma 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. SIRP gamma promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRP gamma targeting with genetic SIRPy knockdown or a SIRP gamma-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, SIRP gamma(hi) 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 SIRP gamma is engaged and reveals that targeting SIRP gamma represents an immune- and CSLC-targeting strategy for lung cancer therapy.