Surgery-induced monocytic myeloid-derived suppressor cells expand regulatory T cells in lung cancer

Abstract

While monocytic myeloid-derived suppressor cells (M-MDSCs) have been reported to induce the development of regulatory T cells (Treg), little is known about their correlation with Treg during perioperative period. Here, we demonstrated that the M-MDSCs expressing CD11b+CD33+HLA-DR–CD14+ in lung cancer patients after thoractomy significantly increased in comparison with preoperation, and their accumulation linearly correlated with an increase in Treg. Surgery-induced M-MDSCs, in addition to have high arginase activity, were more efficient in suppressing T-cell proliferation. Furthermore, the surgery-induced Treg expressed high levels of Foxp3, PD-1 and CTLA-4. Surgery-induced M-MDSCs were more potent in expending Treg when cocultured with autologous T cells in vitro. Using a lung metastasis mouse model, we demonstrated that the M-MDSCs at postoperative period were significantly increased and linearly correlated with Treg. We also showed that all-trans retinoic acid significantly inhibited the induction and proliferation of M-MDSCs, suppressed expansion of Treg, and finally prevented tumor metastasis in the mice after tumor resection. Receiver operating characteristic analyses revealed the superiority of surgery-induced M-MDSCs and Treg to those at preoperative period as a prognostic marker for lung cancer patients. Taken together, our results link the presence of surgery-induced M-MDSCs with the emergence of Treg and identify M-MDSCs and Treg derived postoperatively as potential indicators of tumor metastasis.

Identification of key prognosis-associated genes in the lung adenocarcinoma

“…Furthermore, a previous study has found that M-MDSCs were significantly increased after surgery. Besides, CD33 is involved in inhibiting T cells proliferation and affecting the development of Treg cells, and it is also involved in identifying tumor cells [20] .…”

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

“…TAM regulates immune responses by recruiting Treg into the tumor microenvironment [121]. TAMs are known to recruit natural Treg into tumor tissues by producing chemokines (CC-chemokine ligands: CCL3, CCL4, CCL5, CCL20, CCL22) [122]. Furthermore, by producing IL-10 and TGF-β, TAM activates the transcription factor Foxp3 of CD4+ T cells, possibly contributing to the induction of inducible Treg [121,123].…”

“…Such a state of chronic inflammation may stimulate tumor progression. Furthermore, TAM induces cancer cell migration, infiltration, intravascular invasion and neovascularization needed for tumor growth, and this can lead to tumor metastasis [122]. For example, in breast cancer, CSF-1 secreted from cancer cells and vascular endothelial growth factor (VEGF) secreted from TAM mutually stimulate the secretion of these factors, resulting in the acceleration of tumor infiltration and intravascular invasion [125].…”

“…For example, in breast cancer, CSF-1 secreted from cancer cells and vascular endothelial growth factor (VEGF) secreted from TAM mutually stimulate the secretion of these factors, resulting in the acceleration of tumor infiltration and intravascular invasion [125]. TAM is also involved in remodeling of the tumor microenvironment through the expression of proteases such as matrix metalloproteinase (MMP), cathepsin S, urokinase type plasminogen activation factor, and matrix remodeling enzymes, such as lysyl oxidase and SPARC [122]. These proteases cut the extracellular matrix and create free space around the tumor, thus stimulating the secretion of growth factors, such as heparin-binding epidermal growth factor (HB-EGF) and resulting in tumor infiltration and metastasis [122].…”

“…TAM is also involved in remodeling of the tumor microenvironment through the expression of proteases such as matrix metalloproteinase (MMP), cathepsin S, urokinase type plasminogen activation factor, and matrix remodeling enzymes, such as lysyl oxidase and SPARC [122]. These proteases cut the extracellular matrix and create free space around the tumor, thus stimulating the secretion of growth factors, such as heparin-binding epidermal growth factor (HB-EGF) and resulting in tumor infiltration and metastasis [122].…”