CCR5-related signalling may link peripheral immune activation to brain chemokine responses in breast cancer

Abstract

Peripheral cancers trigger systemic inflammation that impacts the brain, causing cognitive, psychological, and sleep disturbances via cytokine elevation, oxidative stress, glial activation, and impaired neurogenesis. Although chemokine and growth factor increases and immune cell infiltration are well studied in tumour microenvironments, the brain's response to solid peripheral tumours is less understood. We implanted three murine mammary cancer types representing different stages of progression and immune involvement into mice, and measured chemokine and immune growth factor levels in blood and brain tissue (n = 40). Each cancer type induced distinct peripheral changes. CXCL1, associated with neutrophil activation, was the only chemokine elevated in the serum across all cancer types. Triple-negative lines (4T1.2, 67NR) also showed increased IL-2, G-CSF, and GM-CSF, reflecting expansion of neutrophils, myeloid cells, and T cells. In contrast, the EO771 model elevated CCL2, suggesting monocyte/macrophage recruitment into target tissue. However, these peripheral changes were not mirrored in the brain. Instead, levels of CCL5 (which recruits leukocytes), hippocampal levels of IL-12p40 (a macrophage chemoattractant), and IL-12p70 (which activates T cells and natural killer cells) levels were significantly elevated in response to peripheral cancers. These data reveal a prominent serum growth factor signature alluding to enhanced proliferation of hematopoietic progenitor cells in the bone marrow and mobilisation of mature immune cells into circulation. However, the brain's chemokine response suggests selective recruitment of T cells and monocytes/macrophages. Notably, higher serum CCL4 predicted greater hippocampal CCL5 increases, suggesting CCR5-related signalling may draw peripheral immune cells to the brain via increased chemotactic cues.