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

Transforming growth factor beta (TGF beta) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between TGFB1 and genes expressed by myeloid cells, but not granulocytes, in The Cancer Genome Atlas lung adenocarcinoma data, in which high TGFB1 expression was associated with poor survival. To determine whether TGF beta affected cell fate decisions and lineage commitment, we studied primary cultures of CD14 thorn monocytes isolated from peripheral blood of healthy donors. We discovered that TGF beta was a survival factor for CD14 thorn monocytes, which rapidly executed an apoptotic program in its absence. Continued exposure to TGF beta in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 6 (IL6) amplified HLA-DRlowCD14 thorn CD11b thorn CD33 thorn myeloid-derived suppressor cells (MDSCs) at the expense of macrophage and dendritic cell (DC) differentiation. MDSCs generated in the presence of TGF beta were more effective in suppressing T-cell proliferation and promoted the T regulatory cell phenotype. In contrast, inhibition of TGF beta signaling using a small-molecule inhibitor of receptor kinase activity in CD14 thorn 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 TGF beta on myeloid cell survival and lineage commitment suggests that pharmacologic inhibition of TGF beta-dependent signaling in cancer would favor antitumor immunity.