Enzyme controlling metastasis formation discovered. Predicts evolution of metastatic melanoma and chances of survival

https://www.uniupo.it/en/eventi/enzyme-controlling-metastasis-formation-discovered-predicts-evolution-metastatic-melanoma-and

Immunotherapy has been the great change in the treatment of metastatic melanoma, but to date not all patients respond in the same way to the drugs used. A possible breakthrough comes from the results just published in Nature Immunology of a study involving researchers from the Istituto Nazionale dei Tumori di Milano (INT), the Istituto Clinico Humanitas in Rozzano and the Università degli Studi del Piemonte Orientale. The research was supported by the AIRC Foundation for Cancer Research.

 

Abstract

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.

 

Direct link to the article: https://www.nature.com/articles/s41590-021-00921-5