机构：[1]Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA[2]Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China[3]Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院四川省肿瘤医院[4]Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China[5]School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China[6]Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China[7]Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[8]Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, Texas, USA[9]Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA[10]Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, Chongqing, China[11]Wake Forest Innovations, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA
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.
基金：
National Natural Science Foundation of China (no. 81873048 to CX; no. 31991172 to
XWB), Sichuan Provincial Science Fund for Distinguished Young
Scholars of China (no. 2020JDJQ0065), Endowment Funds for Anderson Discovery Professor for Cancer Research, Wake Forest
University School of Medicine Start-up funds, and Catalyst funds
from Wake Innovation Quarter (to HKL).
第一作者机构：[1]Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA[2]Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China[3]Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China[*4]No. 55, Section 4, Renmin South Road, Chengdu, 610042, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA[2]Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China[3]Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China[6]Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China[*1]Medical Center Blvd, Winston-Salem, North Carolina, 27157, USA.[*2]No. 30 Gaotanyan Main Street, Shapingba District, Chongqin, 400038, China[*3]No. 651, Dongfeng Road East, 510060 Guangzhou, China.[*4]No. 55, Section 4, Renmin South Road, Chengdu, 610042, China.
推荐引用方式(GB/T 7714)：
Xu Chuan,Jin Guoxiang,Wu Hong,et al.SIRP gamma-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling[J].JOURNAL OF CLINICAL INVESTIGATION.2022,132(5):doi:10.1172/JCI141797.
APA：
Xu, Chuan,Jin, Guoxiang,Wu, Hong,Cui, Wei,Wang, Yu-Hui...&Lin, Hui-Kuan.(2022).SIRP gamma-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.JOURNAL OF CLINICAL INVESTIGATION,132,(5)
MLA：
Xu, Chuan,et al."SIRP gamma-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling".JOURNAL OF CLINICAL INVESTIGATION 132..5(2022)
医学