Heme catabolism by tumor-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 (F4/80(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-kappa B1-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.

Automated summary

This study identifies a distinct subset of TAMs with high rates of heme catabolism by HO-1, playing a critical role in shaping a prometastatic tumor microenvironment and favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. These TAMs originate from BM precursors, accumulate in the blood of tumor bearers, and preferentially localize at the invasive margin through Nrf2 activation and NF-kappa B1-CSF1R-C3aR axis coordination. Hindering their recruitment or deletion of HO-1 inhibits metastasis formation and enhances anticancer immunotherapy, making them a potential antimetastatic target and prognostic blood marker.