Heme catabolism by tumour-associated macrophages controls metastasis formation

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),