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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499807PMC
http://dx.doi.org/10.1136/jitc-2024-010148DOI Listing

Publication Analysis

Top Keywords

cd8 cells
32
cd93 monocytes
24
infiltration cd8
12
levels cd93
12
monocytes
10
cd8
9
cd93
9
targeting cd93
8
cells
8
solid tumors
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!