分解代谢
癌症研究
转移
化学
巨噬细胞
免疫学
血红素
细胞生物学
生物
生物化学
癌症
新陈代谢
酶
体外
遗传学
作者
Francesca Maria Consonni,Augusto Bleve,Maria Grazia Totaro,Mariangela Storto,Paolo Kunderfranco,Alberto Termanini,Fabio Pasqualini,Chiara Alì,Chiara Pandolfo,Francesco Sgambelluri,Giulia Grazia,Mario Santinami,Andrea Maurichi,Massimo Milione,Marco Erreni,Andrea Doni,Marco Fabbri,Laura Gribaldo,Eliana Rulli,Miguel P. Soares
标识
DOI:10.1038/s41590-021-00921-5
摘要
Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1–CSF1R–C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.
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