title: Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.
abstract: Growing evidence links tumor progression with chronic inflammatory processes and dysregulated activity of various immune cells. In this study, we demonstrate that various types of macrophages internalize microvesicles, called exosomes, secreted by breast cancer and non-cancerous cell lines. Although both types of exosomes targeted macrophages, only cancer-derived exosomes stimulated NF-κB activation in macrophages resulting in secretion of pro-inflammatory cytokines such as IL-6, TNFα, GCSF, and CCL2. In vivo mouse experiments confirmed that intravenously injected exosomes are efficiently internalized by macrophages in the lung and brain, which correlated with upregulation of inflammatory cytokines. In mice bearing xenografted human breast cancers, tumor-derived exosomes were internalized by macrophages in axillary lymph nodes thereby triggering expression of IL-6. Genetic ablation of Toll-like receptor 2 (TLR2) or MyD88, a critical signaling adaptor in the NF-κB pathway, completely abolished the effect of tumor-derived exosomes. In contrast, inhibition of TLR4 or endosomal TLRs (TLR3/7/8/9) failed to abrogate NF-κB activation by exosomes. We further found that palmitoylated proteins present on the surface of tumor-secreted exosomes contributed to NF-κB activation. Thus, our results highlight a novel mechanism used by breast cancer cells to induce pro-inflammatory activity of distant macrophages through circulating exosomal vesicles secreted during cancer progression.
authors.affiliation: Department of Cancer Biology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Amy
authors.initials: A
authors.lastname: Chow
authors.affiliation: 1] Department of Cancer Biology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A [2] Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Weiying
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 1] Department of Cancer Biology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A [2] Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Miranda Y
authors.initials: MY
authors.lastname: Fong
authors.affiliation: 1] Department of Immunology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A [2] City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, 91010, U.S.A.
authors.forename: Jackson
authors.initials: J
authors.lastname: Champer
authors.affiliation: 1] Departments of Molecular Medicine, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A [2] City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, 91010, U.S.A.
authors.forename: Desiree
authors.initials: D
authors.lastname: Van Haute
authors.affiliation: 1] Department of Cancer Biology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A [2] City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, 91010, U.S.A.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Chin
authors.affiliation: Department of Biotherapy and Key Laboratory of Cancer Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: 1] Department of Immunology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A [2] The Mass Spectrometry and Proteomics Core; City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Bogdan Gabriel
authors.initials: BG
authors.lastname: Gugiu
authors.affiliation: Department of Molecular Diabetes Research, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Molecular Diabetes Research, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Stem Cell & Leukemia Research, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Vu
authors.initials: V
authors.lastname: Ngo
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.affiliation: Department of Cancer Biology, City of Hope Beckman Research Institute, Duarte, California, 91010, U.S.A.
authors.forename: Shizhen Emily
authors.initials: SE
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D016207:Cytokines / Q000378:metabolism; D055354:Exosomes / Q000502:physiology*; D005260:Female; D006801:Humans; D056747:Immunomodulation; D061986:MCF-7 Cells; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2