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CD155 regulates tumor growth and susceptibility to T cell mediated killing in diffuse midline glioma
Theophilos Tzaridis1,2, Ester Calvo Fernández3,4,5,6,7, Tanja Eisemann1
1Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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.
Insights
CD155 is a key immune checkpoint in diffuse midline glioma (DMG), a pediatric brain tumor. Targeting CD155 can enhance T cell killing and directly inhibit tumor growth, offering a novel therapeutic strategy.
Area of Science:
- Pediatric Oncology
- Neuro-oncology
- Immunology
Background:
- Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with limited treatment options.
- Current immune checkpoint inhibitors have not improved survival rates for DMG patients.
Purpose of the Study:
- To identify novel immune checkpoint targets in DMG.
- To investigate the therapeutic potential of targeting CD155 in DMG.
Main Methods:
- Screening for immune checkpoint molecules in human and murine DMG.
- Evaluating immune responses to CD155 targeting via co-culture and in vivo studies.
- Assessing the effects of CD155 silencing using whole-transcriptome analysis and in vivo treatments with Thiostrepton.
Main Results:
- CD155 was identified as the most highly expressed immune checkpoint in DMG.
- Silencing CD155 increased T cell-mediated killing and inhibited tumor growth in vivo.
- CD155 silencing induced apoptosis and delayed tumor growth, with FOXM1 identified as a key target.
- Thiostrepton treatment, targeting FOXM1, prolonged survival in DMG-bearing mice.
Conclusions:
- CD155 plays a dual role in regulating immune evasion and tumor growth in DMG.
- Targeting CD155 presents a promising two-pronged therapeutic strategy for diffuse midline glioma.
