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

• Published in: The Journal of clinical investigation 2022-03, Vol.132 (5)
• Main Authors: Xu, Chuan, Jin, Guoxiang, Wu, Hong, Cui, Wei, Wang, Yu-Hui, Manne, Rajesh Kumar, Wang, Guihua, Zhang, Weina, Zhang, Xian, Han, Fei, Cai, Zhen, Pan, Bo-Syong, Hsu, Che-Chia, Liu, Yiqiang, Zhang, Anmei, Long, Jie, Zou, Hongbo, Wang, Shuang, Ma, Xiaodan, Duan, Jinling, Wang, Bin, Liu, Weihui, Lan, Haitao, Xiong, Qing, Xue, Gang, Chen, Zhongzhu, Xu, Zhigang, Furth, Mark E, Molina, Sarah Haigh, Lu, Yong, Xie, Dan, Bian, Xiu-Wu, Lin, Hui-Kuan
• Format: Article
• Language: English
• Subjects: Cancer cells; Cellular signal transduction; Development and progression; Genetic aspects; Immune response; Lung cancer; Membrane proteins
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI141797

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].sup.hi] population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both [SIRP[gamma].sup.hi] and [SIRP[gamma].sup.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 SIRP[gamma] 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'/11 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.