Interferon-g resistance and immune evasion in glioma develop via Notch-regulated co-evolution of malignant and immune cells

Immune surveillance is critical to prevent tumorigenesis. Gliomas evade immune attack, but the underlying mechanisms remain poorly understood. We show that glioma cells can sustain growth independent of im-mune system constraint by reducing Notch signaling. Loss of Notch activity in a mouse model of glioma im-pairs MHC-I and cytokine expression and curtails the recruitment of anti-tumor immune cell populations in favor of immunosuppressive tumor-associated microglia/macrophages (TAMs). Depletion of T cells simu-lates Notch inhibition and facilitates tumor initiation. Furthermore, Notch-depleted glioma cells acquire resistance to interferon-g and TAMs re-educating therapy. Decreased interferon response and cytokine expression by human and mouse glioma cells correlate with low Notch activity. These effects are paralleled by upregulation of oncogenes and downregulation of quiescence genes. Hence, suppression of Notch signaling enables gliomas to evade immune surveillance and increases aggressiveness. Our findings provide insights into how brain tumor cells shape their microenvironment to evade immune niche control.

Automated summary

Gliomas evade immune attack by reducing Notch signaling, leading to impaired MHC-I and cytokine expression, increased TAMs, and increased aggressiveness.