Autocrine TGFβ Is a Survival Factor for Monocytes and Drives Immunosuppressive Lineage Commitment

Abstract

Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between <i>TGFB1</i> and genes expressed by myeloid cells, but not granulocytes, in The Cancer Genome Atlas lung adenocarcinoma data, in which high <i>TGFB1</i> expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14⁺ monocytes isolated from peripheral blood of healthy donors. We discovered that TGFβ was a survival factor for CD14⁺ monocytes, which rapidly executed an apoptotic program in its absence. Continued exposure to TGFβ in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 6 (IL6) amplified HLA-DR^lowCD14⁺CD11b⁺CD33⁺ myeloid-derived suppressor cells (MDSCs) at the expense of macrophage and dendritic cell (DC) differentiation. MDSCs generated in the presence of TGFβ were more effective in suppressing T-cell proliferation and promoted the T regulatory cell phenotype. In contrast, inhibition of TGFβ signaling using a small-molecule inhibitor of receptor kinase activity in CD14⁺ monocytes treated with GM-CSF and IL6 decreased MDSC differentiation and increased differentiation to proinflammatory macrophages and antigen-presenting DCs. The effect of autocrine and paracrine TGFβ on myeloid cell survival and lineage commitment suggests that pharmacologic inhibition of TGFβ-dependent signaling in cancer would favor antitumor immunity.