CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation

Significance Macrophages play a key role in shaping tumor immunity. CCRL2 was originally cloned from LPS-stimulated macrophages; however, whether CCRL2 influences tumor immunity by regulating macrophage function remains unknown. In this study, we identify CCRL2 as a predictive indicator of robust antitumor immunity in human cancers and report the predominant expression of CCLR2 in TAM with immunostimulatory phenotypes. We also reveal the functional role of CCRL2 in potentiating antitumor immunity. Specifically, CCRL2 that is primarily induced by TLR4 agonists in turn interacts with TLR4 to facilitate its retainment in cell surface, thereby amplifying membrane TLR4-mediated downstream inflammatory signaling, finally leading to optimal activation of immunostimulatory macrophages and subsequent antitumor CD8 + T-cell responses.