Interferon-γ orchestrates leptomeningeal anti-tumour response

Area of Science:

• Immunology
• Oncology
• Neuroscience

Background:

• Leptomeningeal metastasis, the spread of solid tumors to the brain's meninges, is a fatal complication.
• Clinical specimens show significant inflammation and interferon gamma (IFNγ) signaling in leptomeningeal metastases.
• The anti-tumor immune response in the leptomeninges is often ineffective.

Purpose of the Study:

• To investigate the role of IFNγ in leptomeningeal metastasis.
• To develop and test therapeutic strategies to overcome the futile anti-tumor response in the leptomeninges.

Main Methods:

• Development of syngeneic mouse models for lung cancer, breast cancer, and melanoma leptomeningeal metastasis.
• Utilized transgenic mice lacking IFNγ or its receptor.
• Employed adeno-associated virus (AAV)-based systems for targeted IFNγ overexpression in the leptomeninges.
• Analyzed immune cell populations including T cells, myeloid cells, dendritic cells (DCs), and natural killer (NK) cells.

Main Results:

• Mice lacking IFNγ or its receptor showed uncontrolled leptomeningeal metastasis growth.
• Leptomeningeal IFNγ overexpression suppressed cancer cell growth independently of adaptive immunity.
• Leptomeningeal T cells producing IFNγ recruit and activate peripheral myeloid cells, generating diverse dendritic cell subsets.
• CCR7+ dendritic cells facilitate NK cell infiltration, proliferation, and cytotoxic activity, controlling tumor growth.

Conclusions:

• Leptomeningeal metastasis involves a unique, space-specific IFNγ signaling pathway.
• IFNγ-mediated recruitment and activation of myeloid cells and NK cells are crucial for controlling leptomeningeal tumor growth.
• This pathway suggests a potential immune-therapeutic approach for treating leptomeningeal metastases.