T cell cytokines found to influence tumor-immune interactions in metastases

 Memorial Sloan Kettering Cancer Center investigators report that T cell interferon-γ (IFNγ) orchestrates a dendritic-cell–natural-killer-cell circuit that suppresses leptomeningeal metastases in mouse models.

Findings suggest that IFNγ-driven recruitment and activation of dendritic cells in the cerebrospinal fluid-filled leptomeninges mobilizes natural killer cells to target and eliminate cancer cells, revealing a potential therapeutic mechanism against metastatic cancer spread in the central nervous system.

Leptomeningeal metastasis (LM) is a severe consequence of advanced cancers such as breast, lung, and melanoma, characterized by the infiltration of cancer cells into the cerebrospinal fluid-filled leptomeninges. LM provokes substantial immune infiltration, generating a dense network of leukocytes and inflammatory cytokines within the central nervous system.

Previous studies examining the immune landscape of LM reveal intricate signaling interactions between tumor and immune cells, suggesting that cancer cells may engage cytokine networks to influence immune dynamics in this compartment.

In the study, "Interferon-γ orchestrates leptomeningeal anti-tumour response," published in Nature, researchers developed syngeneic lung, breast, and melanoma mouse models to examine IFNγ signaling within the leptomeninges.

Mouse models included two genetic backgrounds and six leptomeningeal metastasis lines derived from lung, breast, and melanoma cancer cells.

Analyses encompassed 27,062 single cells from murine cerebrospinal fluid and 17,218 single cells from patient cerebrospinal fluid. Patient samples included cerebrospinal fluid from individuals with breast, lung, and melanoma cancer, with and without leptomeningeal metastases, to assess immune cell populations and cytokine profiles.

Immune cell composition and cytokine profiles in cerebrospinal fluid samples were assessed using proteomic and single-cell transcriptomic analyses. Flow cytometry and scRNA-seq were employed to quantify immune populations and cytokine expression in both mouse and human samples.

Host mice deficient in IFNγ receptors showed uncontrolled leptomeningeal tumor growth, yet subcutaneous or orthotopic tumors remained unchanged.

T cells emerged as the primary source of IFNγ within the leptomeninges. Adeno-associated-virus-mediated overexpression of the gene encoding IFNγ reduced tumor burden without inducing neurotoxicity.

Proteogenomic analysis identified IFNγ as a driver of conventional dendritic cell type 2 maturation into migratory dendritic cells, which secreted cytokines Interleukin-12 and Interleukin-15. These cytokines promoted natural killer (NK) cell proliferation and cytotoxicity.

Depleting NK cells abrogated IFNγ's anti-tumor effect, while dendritic-cell-specific gene deletion (of Ifngr1) restored tumor progression. Cancer-cell-intrinsic IFNγ signaling was not required for tumor suppression.

The findings reveal a promising new strategy for tackling cancer that spreads to the brain's protective membranes, a condition that remains challenging to treat with existing therapies. By leveraging the body's own immune signals, specifically IFNγ, it may be possible to activate immune cells that can track down and eliminate cancer cells hiding in hard-to-reach areas.

If future studies confirm these results in humans, the knowledge gained could have therapeutic applications for patients with metastatic breast, lung, and melanoma cancers, offering new hope for slowing disease progression and improving survival.

More information: Jan Remsik et al, Interferon-γ orchestrates leptomeningeal anti-tumour response, Nature (2025). DOI: 10.1038/s41586-025-09012-z

https://medicalxpress.com/news/2025-05-cell-cytokines-tumor-immune-interactions.html