Immunosuppressive myeloid cells induce mesenchymal-like breast cancer stem cells by a membrane-bound TGF-β1-dependent mechanism.

Suppressive myeloid cells play a central role in cancer escape from anti-tumor immunity and exert multiple pro-tumoral activities, including the promotion of cancer cell survival, invasion, and metastasis. Recent evidence suggests that certain subsets may also influence tumor heterogeneity and cellular plasticity. However, their role in cancer stem cell promotion and plasticity and the underlying molecular mechanisms have yet to be deciphered. Here we demonstrate that human immunosuppressive myeloid cells, generated in vitro or isolated from patients with breast cancer, induce cancer stem-like cells exhibiting mesenchymal features. This cancer-stemness-inducing function was restricted to a CD52-expressing myeloid subset. Single cell transcriptomic- and surface proteome-based interactome analyses identify membrane-bound TGF-β1 as a potential mediator of this effect. Functional inhibition of the TGF-β1 pathway blocks stem-like feature induction by suppressive myeloid cells. These results provide insights into the cancer stemness-promoting capacity of suppressive myeloid cells and its associated molecular mechanisms in breast cancer.