Targeting CD93 on Monocytes revitalizes Anti-Tumor Immunity by Enhancing the Function and Infiltration of CD8+ T Cells

In this study, we found that monocytes in the peritumoral tissues of HCC significantly increased levels of CD93 expression, and these CD93+ monocytes collocated with CD8+ T cells, whose density was much higher in peri-tumor than intra-tumor areas. In vitro experiments showed that glycolytic switch mediated tumor-induced CD93 up-regulation in monocytes via the Erk signaling pathway. CD93 on the one hand could enhance PD-L1 expression through the AKT-GSK3β axis, while on the other hand induce monocytes to produce versican, a type of matrix component which interacted with hyaluronan and collagens to inhibit CD8+ T cell migration. Consistently, levels of CD93+ monocytes positively correlated with the density of peritumoral CD8+ T cells while negatively correlated with that of intratumoral CD8+ T cells. Targeting CD93 on monocytes not only increased the infiltration and activation of CD8+ T cells, but also enhanced tumor sensitivity to anti-PD-1 treatment in mice in vivo. Levels of CD93 expression on monocytes from paired nontumor, peri-tumor and tumor tissues of human hepatocellular carcinoma (HCC) were evaluated. The underlying mechanisms mediating effects of CD93+ monocytes on the inhibition and tumor exclusion of CD8+ T cells were studied through both in vitro and in vivo experiments.