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.
CONSONNI Francesca Maria;
BLEVE Augusto;
TOTARO Maria Grazia;
STORTO Mariangela;
KUNDERFRANCO Paolo;
TERMANINI Alberto;
PASQUALINI Fabio;
ALI' Chiara;
PANDOLFO Chiara;
SGAMBELLURI Francesco;
GRAZIA Giulia;
SANTINAMI Mario;
MAURICHI Andrea;
MILIONI Massimo;
ERRENI Marco;
DONI Andrea;
FABBRI Marco;
GRIBALDO Laura;
RULLI Eliana;
PARREIRA SOARES Miguel;
TORRI Valter;
MORTARINI Roberta;
ANICHINI Andrea;
SICA Antonio;
2021-07-08
NATURE PUBLISHING GROUP
JRC119623
1529-2908 (online),
https://www.nature.com/articles/s41590-021-00921-5,
https://publications.jrc.ec.europa.eu/repository/handle/JRC119623,
10.1038/s41590-021-00921-5 (online),
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