RB1 Regulates Myeloid-Derived Suppressor Cell Differentiation

Aberrant myelopoiesis promotes the expansion of myeloid-derived suppressor cells (MDSC) that lack markers of mature macrophages and dendritic cells (DC) and stimulate tumor growth by inhibiting anticancer immune responses. MDSCs consist of 2 subgroups, monocytic MDSCs (M-MDSC) and polymorphonuclear MDSCs (PMN-MDSC), which differ in their morphology and expression profiles. These cells have been proposed to develop from monocyte and granulocyte progenitors, respectively, but the mechanisms underlying MDSC differentiation in tumors are unclear. Youn and colleagues detected an accumulation of PMN-MDSCs but not M-MDSCs in murine tumor models and in patients with various types of cancer. This expansion did not occur via increased proliferation of PMN-MDSCs or neutrophil precursors but required the differentiation of M-MDSCs from tumor-bearing mice into PMN-MDSCs. Unlike monocytes, most M-MDSCs did not generate macrophages or DCs but instead acquired morphologic and functional properties of PMN-MDSCs, including cell surface expression of lymphocyte antigen 6 complex, locus G (Ly6G), production of reactive oxygen species, and immunosuppressive activity. Intriguingly, retinoblastoma 1 (Rb1) expression was decreased in PMN-MDSCs of tumor-bearing mice and in a subset of weakly proliferative M-MDSCs capable of generating Ly6G-positive cells, as well as in PMN-MDSCs from patients with cancer, suggesting that RB1 may modulate myeloid differentiation. Indeed, deletion of Rb1 in mice stimulated the differentiation of monocytes into PMN-MDSCs, whereas Rb1 overexpression in murine M-MDSCs diminished PMN-MDSC accumulation in favor of increased macrophage and DC differentiation. This reduction in Rb1 expression was mediated by histone deacetylase-2 (HDAC2)–driven epigenetic silencing of the Rb1 promoter, and treatment with HDAC inhibitors triggered differentiation of M-MDSCs into macrophages and DCs. These results implicate RB1 as a critical regulator of myeloid differentiation and suggest that targeted blockade of HDAC 2 may redirect this process to limit the expansion of tumor-promoting MDSCs.

Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 2013;14:211–20.

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