Beatriz de Alves Pereira: There and Back Again: CD93 at the Center of Tumor-Endothelial-Immune Crosstalk

Abstract

The vasculature is a crucial element  of the tumor microenvironment, enabling tumors to sustain their elevated metabolic needs. Furthermore, it can act as significant hurdle to effective anti-tumor immune responses, by acting as a barrier to immune cell infiltration. Thus, the tumor-associated vasculature has become an attractive therapeutic target, both for its anti-cancer and immune-modulating potential.

CD93 is a single-pass transmembrane glycoprotein with low physiological expression in adulthood that is upregulated on endothelial cells in multiple solid tumors. Its overexpression correlates with poor prognosis in human cancers, including glioma, whereas genetic deletion improves survival in several murine tumor models. However, CD93 also contributes to maintenance of the vascular barrier, underscoring the complexity of its therapeutic targeting.

The work presented in this thesis aims to elucidate the role of CD93 in the regulation of vascular function in tumor setting. In particular, we assessed its contribution to tumor progression in both metastatic and non-metastatic cancers, as well as its interplay with components of the TME, including the ECM, tumor cells and immune cells. Moreover, these studies also explored the potential of CD93 as a therapeutic target for cancer therapy.

In Paper I, we studied the role of CD93 in vascular integrity in metastatic tumors, where we determined its loss to be beneficial with regard to reduction in primary tumor growth, but detrimental in terms of elevated metastatic dissemination. We additionally described a novel signaling axis, where CD93 contributes to limiting VEGFR2 signaling by recruiting VE-PTP, leading to junction stabilization.

In Paper II, we examined the contribution of endothelial CD93 to perivascular invasion in glioma. Endothelial deletion or antibody-mediated blockade of CD93 impaired this invasion route. Anti-CD93 treatment prolonged survival in glioma-bearing mice and enhanced chemotherapy-induced glioma cell apoptosis, supporting disruption of the perivascular niche as a therapeutic strategy.

In Paper III, we explored CD93 at the immune-vascular interface in glioma. Endothelial CD93 deletion promoted endothelial activation and immune cell infiltration via a previously uncharacterized RhoA/ROCK-dependent modulation of NF-κB signaling. CD93 loss also induced formation of T cell-rich perivascular immune hubs conducive to T cell priming, resulting in improved response to checkpoint blockade.

Overall, CD93 remains an attractive target for multimodal modulation of the tumor microenvironment, both from the vascular and leukocytic points of view. The work this thesis comprises will aid in further understanding the multifaceted roles of CD93 in cancer and, in the future, help to lay the foundations for its use as a therapeutic option.