CD155 regulates tumor growth and susceptibility to T cell mediated killing in diffuse midline glioma
Theophilos Tzaridis, Ester Calvo Fernández, Tanja Eisemann, Angela Liou, Augusto Faria Andrade, Carlos A O de Biagi-Junior, Jennifer L Hope, Liam S Hewson, Michael McNicholas, Antonella De Cola, Manav Pathania, Oren J Becher, Nada Jabado, Jon D Larson, Suzanne J Baker, Andrea Califano, Anindya Bagchi, Matthew Gallitto, Cynthia Hawkins, Mariella G Filbin, Linda M Bradley, Peter D Adams, Jovana Pavisic, Robert J Wechsler-ReyaAbstract
Background
Diffuse midline glioma (DMG) is a devastating pediatric brain tumor with an unmet need for novel therapies. Immune checkpoint inhibitors have failed to prolong survival of DMG patients.
Methods
In this study, we screened for immune checkpoint molecules in DMG, evaluated immunological responses to checkpoint targeting by co-culture assays and depletion of immune cells in vivo, studied the effects of CD155 silencing by whole-transcriptome analyses and performed in vivo treatments with Thiostrepton.
Results
In human and murine DMG cells, as well as primary brain tumor samples, we identified CD155 as the most highly expressed immune checkpoint. When murine DMG cells were co-cultured with CD8+ T cells, silencing of CD155 led to a marked increase in T cell-mediated killing. Strikingly, CD155-deficient DMG cells failed to grow in immunocompetent mice, and depletion of CD8+ T cells allowed these tumors to grow. CD155 also exerted cell-autonomous effects on tumor cells: silencing of CD155 led to induction of apoptosis of DMG cells and delayed tumor growth in immunodeficient mice. Transcriptomic analyses identified FOXM1 as a key target of CD155. Notably, FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo. Finally, treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting agent, delayed tumor growth and prolonged survival.
Conclusions
These studies demonstrate that CD155 regulates immune evasion and tumor growth in DMG, and suggest that targeting CD155 could be a valuable two-pronged therapeutic strategy for this disease.