title: CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer.
abstract: Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIM), including CD11b (ITGAM)(+)F4/80 (EMR1)+ tumor-associated macrophages (TAM), and CD11b(+)Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSC), respond to cancer-related stresses and play critical roles in promoting tumor angiogenesis, tissue remodeling, and immunosuppression. In this report, we used a prostate cancer model to investigate the effects of irradiation on TAMs and MDSCs in tumor-bearing animals. Unexpectedly, when primary tumor sites were irradiated, we observed a systemic increase of MDSCs in spleen, lung, lymph nodes, and peripheral blood. Cytokine analysis showed that the macrophage colony-stimulating factor CSF1 increased by two-fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy. Mechanistic investigations revealed the recruitment of the DNA damage-induced kinase ABL1 into cell nuclei where it bound the CSF1 gene promoter and enhanced CSF1 gene transcription. When added to radiotherapy, a selective inhibitor of CSF1R suppressed tumor growth more effectively than irradiation alone. Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of TIMs that can limit the efficacy of radiotherapy. Furthermore, they suggest that CSF1 inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes.
authors: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1735, USA.
authors: Jingying
authors: J
authors: Xu
authors: Jemima
authors: J
authors: Escamilla
authors: Stephen
authors: S
authors: Mok
authors: John
authors: J
authors: David
authors: Saul
authors: S
authors: Priceman
authors: Brian
authors: B
authors: West
authors: Gideon
authors: G
authors: Bollag
authors: William
authors: W
authors: McBride
authors: Lily
authors: L
authors: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D022423:Myeloid Cells / Q000166:cytology*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D011878:Radiotherapy / Q000379:methods; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D016186:Receptor, Macrophage Colony-Stimulating Factor