Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis
Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis
SUMMARY Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant non-malignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. We used an inhibitor of colony stimulating factor 1 receptor (CSF1R) to target TAMs at distinct stages of the metastatic cascade in preclinical breast-to-brain metastasis models and found that CSF1R inhibition leads to anti-tumor responses in prevention and intervention trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuro-inflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, combined blockade of CSF1R and STAT5 signaling led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.
Sch?ffer Alexander、Salamero-Boix Anna、Alekseeva Tijna、Elie Benelita T.、Daniel Roy T.、Plate Karl H.、Hegi Monika E.、Maas Roeltje R.、Schulz Michael、Groth Marie、Zeiner Pia S.、Zinke Jenny、Joyce Johanna A.、Harter Patrick N.、Niesel Katja、Sevenich Lisa、Bowman Robert L.、Klemm Florian
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental TherapyGeorg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy||Biological Sciences, Faculty 15, Goethe University FrankfurtGeorg-Speyer-Haus, Institute for Tumor Biology and Experimental TherapyCancer Biology and Genetics Program, Memorial Sloan Kettering Cancer CenterDepartment of Neurosurgery, Centre Hospitalier Universitaire VaudoisInstitute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt||German Cancer Research Center (DKFZ)||German Cancer Consortium (DKTK)||Frankfurt Cancer Institute (FCI), Goethe University FrankfurtNeuroscience Research Center, Centre Hospitalier Universitaire Vaudois||Department of Neurosurgery, Centre Hospitalier Universitaire VaudoisDepartment of Oncology, University of Lausanne||Ludwig Institute for Cancer Research||Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois||Department of Neurosurgery, Centre Hospitalier Universitaire VaudoisGeorg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy||Biological Sciences, Faculty 15, Goethe University FrankfurtCancer Biology and Genetics Program, Memorial Sloan Kettering Cancer CenterInstitute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt||Dr. Senckenberg Institute of Neurooncology, Goethe University FrankfurtInstitute of Neurology (Edinger Institute), Goethe University Hospital FrankfurtDepartment of Oncology, University of Lausanne||Ludwig Institute for Cancer ResearchInstitute of Neurology (Edinger Institute), Goethe University Hospital Frankfurt||German Cancer Research Center (DKFZ)||German Cancer Consortium (DKTK)||Frankfurt Cancer Institute (FCI), Goethe University FrankfurtGeorg-Speyer-Haus, Institute for Tumor Biology and Experimental TherapyGeorg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy||German Cancer Research Center (DKFZ)||German Cancer Consortium (DKTK)||Frankfurt Cancer Institute (FCI), Goethe University FrankfurtCancer Biology and Genetics Program, Memorial Sloan Kettering Cancer CenterDepartment of Oncology, University of Lausanne||Ludwig Institute for Cancer Research
肿瘤学神经病学、精神病学基础医学
Sch?ffer Alexander,Salamero-Boix Anna,Alekseeva Tijna,Elie Benelita T.,Daniel Roy T.,Plate Karl H.,Hegi Monika E.,Maas Roeltje R.,Schulz Michael,Groth Marie,Zeiner Pia S.,Zinke Jenny,Joyce Johanna A.,Harter Patrick N.,Niesel Katja,Sevenich Lisa,Bowman Robert L.,Klemm Florian.Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2021.06.07.447034.点此复制
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