Heme catabolism by tumor-associated macrophages controls metastasis formation

• Published in: Nature immunology Vol. 22; no. 5; pp. 595 - 606
• Main Authors: Consonni, Francesca Maria, Bleve, Augusto, Totaro, Maria Grazia, Storto, Mariangela, Kunderfranco, Paolo, Termanini, Alberto, Pasqualini, Fabio, Alì, Chiara, Pandolfo, Chiara, Sgambelluri, Francesco, Grazia, Giulia, Santinami, Mario, Maurichi, Andrea, Milione, Massimo, Erreni, Marco, Doni, Andrea, Fabbri, Marco, Gribaldo, Laura, Rulli, Eliana, Soares, Miguel Parreira, Torri, Valter, Mortarini, Roberta, Anichini, Andrea, Sica, Antonio
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2021; Nature Publishing Group
• Subjects: 631/250; 631/250/580; Angiogenesis; Animals; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - blood; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Blood; Bone marrow; Cancer; Cell Line, Tumor - transplantation; Cellular signal transduction; Chemotherapy, Adjuvant - methods; Complement component C3a; Complement receptors; Development and progression; Disease Models, Animal; Epithelial-Mesenchymal Transition - immunology; Female; Genetic aspects; Health aspects; Heme; Heme - metabolism; Heme oxygenase (decyclizing); Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - blood; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hemopoiesis; Heterogeneity; Humans; Immunology; Immunosuppression; Immunotherapy; Infectious Diseases; Invasiveness; Kaplan-Meier Estimate; Lung Neoplasms - immunology; Lung Neoplasms - mortality; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Macrophages; Male; Melanoma; Melanoma - immunology; Melanoma - mortality; Melanoma - secondary; Melanoma - therapy; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mesenchyme; Metastases; Metastasis; Mice; Mice, Transgenic; Monocytes; Myeloid Progenitor Cells - immunology; Myeloid Progenitor Cells - metabolism; Osteoprogenitor cells; Oxygenase; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Tumor Escape - drug effects; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; Tumors; Italy
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-021-00921-5

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 (F4/80 hi CD115 hi C3aR hi CD88 hi ), 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. Tumor-associated macrophages (TAMs) play multifaceted roles in establishing an immunosuppressive tumor microenvironment. Sica and colleagues find that macrophage-intrinsic complement signaling initiates a pathway leading to the induction of highly tumorigenic TAMs.