Table 2.
Mediators (soluble mediators or exosomes) of the effects of EMT tumor cells on cells of the immune system.
| Mediator | Summary of Experimental Observations. | References |
|---|---|---|
| Cytokines | ||
| IL-2 | IL-2 from cholangiocarcinoma cells with EMT-like features induced generation of CD4+ CD25+ natural Tregs. | [46] |
| IL-6 | IL-6 induced macrophages to differentiate into M2-polarized macrophages. | [60] |
| TGF-β | TGF-β from cholangiocarcinoma cells with EMT-like features induced generation of CD4+ CD25+ natural Tregs. | [46] |
| BMP-4 | Recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines promoted monocyte/macrophage polarization toward an M2 phenotype. | [49] |
| GM-CSF | GM-CSF from mesenchymal-like breast cancer cells (BT-549, MDA-MB-436, and MDA-MB-231) promoted the acquisition of a TAM-like phenotype by macrophages. | [51] |
| Chemokines | ||
| IL-8/CXCL8 | IL-8 from claudin-low TNBC cells induced recruitment of PMN-MDSCs in vitro and in vivo, as determined through neutralization experiments with mAb HuMax-IL8. | [42] |
| CXCL1, CXCL2 | CXCL1 and CXCL2 from mouse ovarian cancer cells promoted tumor infiltration of MDSCs, as determined by knockdown of EMT transcription factor Snail. | [48] |
| CCL2 | CCL2 derived from various tumor cell lines induced, in cooperation with Lipocalin-2, DCregs, which in turn induced Tregs, and finally impaired the induction of tumor-specific CTLs. | [53] |
| CCL20 | CCL20 derived from EMT hepatoma cells induced IDO in monocyte-derived macrophages, which in turn suppressed T-cell proliferations and promoted the expansion of Tregs. | [50] |
| Other Soluble Mediators | ||
| Thrombospondin-1 | Snail-transduced melanoma cells with EMT features produced thrombospondin-1, which induced Tregs and impaired DCs in vitro and in vivo. | [52] |
| Lipocalin-2 | CCL2 derived from various tumor cell lines induced, in cooperation with Lipocalin-2, DCregs, which in turn induced Tregs and finally impaired the induction of tumor-specific CTLs. | [53] |
| Exosomes | ||
| Snail-expressing EMT human head and neck cancer cells activated the transcription of miR-21 to produce tumor-derived exosomes, which were engulfed by CD14+ human monocytes, suppressing the expression of M1 markers and increasing that of M2 markers. | [61] | |
Abbreviations: BMP, bone morphogenetic protein; CCL, C-C motif chemokine ligand; CTL, cytotoxic T lymphocyte; CXCL, C-X-C motif chemokine ligand; DCreg, regulatory dendritic cell; GM-CSF, granulocyte–macrophage colony-stimulating factor; ICAM, intercellular adhesion molecule; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; MDSC, myeloid-derived suppressor cell; miR-21, micro-RNA; PAI, plasminogen activator inhibitor; PMN, polymorphonuclear; TAM, tumor-associated macrophage; TGF, transforming growth factor; TNBC, triple-negative breast cancer; Treg, regulatory T cell.