Autor: |
Kosti CN; Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Vaitsi PC; Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Pappas AG; Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Iliopoulou MP; Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Psarra KK; Department of Immunology - Histocompatibility, Evangelismos Hospital, Athens, Greece., Magkouta SF; Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Kalomenidis IT; Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. |
Abstrakt: |
Malignant pleural effusion (MPE) is an incurable common manifestation of many malignancies. Its formation is orchestrated by complex interactions among tumor cells, inflammatory cells, and the vasculature. Tumor-associated macrophages present the dominant inflammatory population of MPE, and M2 macrophage numbers account for dismal prognosis. M2 polarization is known to be triggered by CSF1/CSF1 receptor (CSF1R) signaling. We hypothesized that CSF1R+ M2 macrophages favor MPE formation and could be therapeutically targeted to limit MPE. We generated mice with CSF1R-deficient macrophages and induced lung and colon adenocarcinoma-associated MPE. We also examined the therapeutic potential of a clinically relevant CSF1R inhibitor (BLZ945) in lung and colon adenocarcinoma-induced experimental MPE. We showed that CSF1R+ macrophages promoted pleural fluid accumulation by enhancing vascular permeability, destabilizing tumor vessels, and favoring immune suppression. We also showed that CSF1R inhibition limited MPE in vivo by reducing vascular permeability and neoangiogenesis and impeding tumor progression. This was because apart from macrophages, CSF1R signals in cancer-associated fibroblasts leading to macrophage inflammatory protein 2 secretion triggered the manifestation of suppressive and angiogenic properties in macrophages upon CXCR2 paracrine activation. Pharmacological targeting of the CSF1/CSF1R axis can therefore be a vital strategy for limiting MPE. |