Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain

Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.

Automated summary

Brain metastasis in breast cancer is difficult to treat, but the development of new therapies is of utmost clinical relevance. Toll-like receptor 4 (TLR4) has been correlated with poor prognosis, but its role in breast cancer brain metastasis has not been investigated. This study tested the prognostic value of various TLRs and examined their therapeutic potential. The results revealed the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Additionally, TLR1 and IL6 were found to be associated with poor overall survival in breast cancer brain metastasis patients. Lastly, a single LPS application was shown to shape the microglia/macrophage reaction and reduce metastatic infiltration in the brain, suggesting potential implications for immunotherapy.