Targeting CD93 on monocytes revitalizes antitumor immunity by enhancing the function and infiltration of CD8+ T cells

Background: Limited activation and infiltration of CD8⁺ T cells are major challenges facing T cell-based immunotherapy for most solid tumors, of which the mechanism is multilayered and not yet fully understood.

Methods: Levels of CD93 expression on monocytes from paired non-tumor, peritumor 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.

Results: 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 peritumor than intratumor areas. In vitro experiments showed that glycolytic switch mediated tumor-induced CD93 upregulation 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 inducing 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.

Conclusion: This study identified an important mechanism contributing to the activation and limited infiltration of CD8⁺ T cells in solid tumors, and CD93⁺ monocytes might represent a plausible immunotherapeutic target for the treatment of HCC.

Hepatocellular Carcinoma; Immunotherapy; Macrophage; Monocyte; Tumor microenvironment - TME.