Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain
Blazquez R, Chuang HN, Wenske B, Trigueros L, Wlochowitz D, Liguori R, Ferrazzi F, Regen T, Proescholdt MA, Rohde V, Riemenschneider MJ, Stadelmann C, Bleckmann A, Beissbarth T, Van Rossum D, Hanisch UK, Pukrop T (2022)
Publication Type: Journal article
Publication year: 2022
Journal
DOI: 10.1038/s41388-022-02496-3
Abstract
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.
Authors with CRIS profile
Renato Liguori
Sonderforschungsbereich/Transregio 305/1: Über die Analyse der metastatischen Koloniebildung zu neuen systemischen Krebstherapien
Fulvia Ferrazzi
Department of Nephropathology
Involved external institutions
Universitätsklinikum Regensburg
Germany (DE)
Universitätsklinikum Göttingen
Germany (DE)
Georg-August-Universität Göttingen
Germany (DE)
Germany (DE)
Universitätsklinikum Göttingen
Germany (DE)
Georg-August-Universität Göttingen
Germany (DE)
How to cite
APA:
Blazquez, R., Chuang, H.-N., Wenske, B., Trigueros, L., Wlochowitz, D., Liguori, R.,... Pukrop, T. (2022). Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain. Oncogene. https://doi.org/10.1038/s41388-022-02496-3
MLA:
Blazquez, Raquel, et al. "Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain." Oncogene (2022).
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