A YAP/TAZ-CD54 axis is required for CXCR2 −CD44 − tumor-specific neutrophils to suppress gastric cancer
Pingping Nie, Weihong Zhang, Yan Meng, Moubin Lin, Fenghua Guo, Hui Zhang, Zhenzhu Tong, Meng Wang, Fan Chen, Liwei An, Yang Tang, Yi Han, Ruixian Yu, Wenjia Wang, Yuanzhi Xu, Linxin Wei, Zhaocai Zhou, Shi Jiao
Abstract
As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.