Leptomeningeal metastases (LM) are a fatal complication of cancer, where tumor cells infiltrate the meninges of the brain and spinal cord, which is most often observed in breast cancer, lung cancer, and melanoma.
CNS metastases typically arise under conditions of immune suppression, where immune cells either are absent or fail to control the tumor. Unlike other CNS metastases, LM provoke strong inflammatory responses and active immune cell infiltration. Clinically, LM resembles infectious meningitis. Despite the immune cell abundance and inflammation, tumor cells survive and adapt to the environment. Research shows inflammation alters tumor gene activity, promoting survival.
Why such a robust immune response is ineffective remains unclear. Prior studies show that immune cells in LM behave atypically. For example, macrophage gene expression is altered. Inflammatory cytokine levels differ between cerebrospinal fluid (CSF) and plasma, indicating unique CNS immune regulation.
Memorial Sloan Kettering Cancer Center researchers conducted a comprehensive analysis of LM antitumor immunity in both human samples and mouse models.
They found that interferon-gamma (IFNγ) is the key immune mediator in the leptomeningeal space but works unusually. Instead of activating macrophages, IFNγ induces maturation of cDC2 dendritic cells, which produce cytokines that stimulate NK cells. These cytokines — IL-12 and IL-15 — sustain NK cell survival and proliferation.
The primary sources of IFNγ are T cells and NK cells. IFNγ suppresses tumors not by acting directly on cancer cells but by stimulating surrounding immune cells. Tumor cells remain responsive to IFNγ signals, but these signals do not directly inhibit their proliferation.
In mouse models, deleting IFNγ or its receptor significantly impaired tumor control. Conversely, administering IFNγ slowed tumor growth. In a follow-up experiment, scientists used an adenoviral vector to induce IFNγ expression in the leptomeningeal space. This approach markedly inhibited LM progression without causing neuroinflammation or degeneration, increasing T cell, NK cell, and dendritic cell infiltration.
IFNγ enhances tumor visibility outside the CNS by promoting MHC class I and II antigen presentation. Surprisingly, in the leptomeningeal space, IFNγ functioned independently of adaptive immunity, monocytes, or macrophages. Instead, cDCs were its main target.
In immune-deficient mice, the antitumor effect of IFNγ was lost. However, the effect remained in mice lacking antigen presentation, confirming that IFNγ works independently of adaptive immune responses. The tumor-suppressive effect also did not depend on IFNγ responsiveness in macrophages, monocytes, or neutrophils — only dendritic cells were required.
Removing cDCs accelerated tumor growth. Even in the presence of IFNγ, the absence of cDCs abolished the antitumor effect. Specifically, cDC2 cells responded to IFNγ by maturing into CCR7+ DCs and accumulating in the leptomeningeal space.
These CCR7+ DCs secreted IL-12 and IL-15 cytokines under the influence of IFNγ, promoting NK cell activation and persistence. In CSF from LM patients, elevated IL-12 and IL-15 levels were also observed, suggesting a similar mechanism in humans.
NK cells are essential for the antitumor activity of IFNγ. If NK cells were depleted, IFNγ lost its tumor-suppressing effect. Thus, NK cells act as the primary IFNγ-responsive effectors in LM.
Their effectiveness depends on cytokines released by CCR7+ dendritic cells rather than direct IFNγ signaling. Mice lacking the IFNγ receptor in NK cells showed impaired proliferation due to cytokine deficiency, not intrinsic defects.
Previous attempts to treat LM by targeting adaptive immunity have been largely unsuccessful. These findings highlight that activating the innate immune response via DC and NK cell stimulation could offer a more effective strategy for LM treatment.
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Reference
Interferon-γ orchestrates leptomeningeal anti-tumour response
