ID #928 CD155 regulates tumor growth and immune evasion in diffuse midline glioma

Abstract

There is an unmet need for effective treatment strategies for diffuse midline glioma (DMG), a devastating pediatric brain tumor. Clinical trials with immune checkpoint inhibitors that are efficacious in other tumors have failed to show a survival benefit for DMG patients. In this study, we analyzed the expression of several known immune checkpoint molecules in human and murine DMG cells by flow cytometry and found that the poliovirus receptor CD155 (an adhesion molecule that interacts with CD96 and TIGIT on CD8+ T cells) is highly expressed in all DMG lines and models. This finding was confirmed in primary pediatric brain tumor samples. To test whether CD155 regulates susceptibility to CD8+ T cell killing, we cultured murine DMG cells with CD8+ T cells. shRNA mediated silencing of CD155 led to a marked increase in T cell-mediated killing in vitro. Strikingly, CD155-deficient DMG cells failed to grow at all in immunocompetent mice, while depletion of CD8+ T cells allowed these tumors to grow. Intriguingly, CD155 also exerted cell-autonomous effects on tumor cells: silencing of CD155 led to induction of apoptosis of DMG cells even in the absence of T cells and led to delayed tumor growth even in immunocompromised mice. Transcriptomic analyses identified the transcription factor FOXM1 as a key target that is silenced in CD155-deficient cells. FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo, and treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting antibiotic, delayed tumor growth and prolonged survival. These studies demonstrate that CD155 functions as a modulator of tumor cell sensitivity to T cells and also regulates tumor cell survival in a T cell-independent manner. Our studies suggest that targeting CD155 or its downstream mediators could be a valuable double-pronged therapeutic strategy for this devastating disease.