Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis.

Autor: Klemm F; Department of Oncology, University of Lausanne, Lausanne, Switzerland.; Ludwig Institute for Cancer Research, Lausanne, Switzerland., Möckl A; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany., Salamero-Boix A; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.; Biological Sciences, Faculty 15, Goethe University Frankfurt, Frankfurt am Main, Germany., Alekseeva T; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany., Schäffer A; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany., Schulz M; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.; Biological Sciences, Faculty 15, Goethe University Frankfurt, Frankfurt am Main, Germany., Niesel K; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany., Maas RR; Department of Oncology, University of Lausanne, Lausanne, Switzerland.; Ludwig Institute for Cancer Research, Lausanne, Switzerland.; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland., Groth M; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Elie BT; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Bowman RL; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hegi ME; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland., Daniel RT; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland., Zeiner PS; Institute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.; Dr. Senckenberg Institute of Neurooncology, Goethe University Frankfurt, Frankfurt am Main, Germany., Zinke J; Institute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany., Harter PN; Institute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.; Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany., Plate KH; Institute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.; Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany., Joyce JA; Department of Oncology, University of Lausanne, Lausanne, Switzerland. johanna.joyce@unil.ch.; Ludwig Institute for Cancer Research, Lausanne, Switzerland. johanna.joyce@unil.ch., Sevenich L; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany. sevenich@gsh.uni-frankfurt.de.; German Cancer Research Center (DKFZ), Heidelberg, Germany. sevenich@gsh.uni-frankfurt.de.; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany. sevenich@gsh.uni-frankfurt.de.; Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany. sevenich@gsh.uni-frankfurt.de.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2021 Oct; Vol. 2 (10), pp. 1086-1101. Date of Electronic Publication: 2021 Oct 18.
DOI: 10.1038/s43018-021-00254-0
Abstrakt: Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant nonmalignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuroinflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, blockade of CSF1R combined with inhibition of STAT5 signaling via AC4-130 led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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