TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment

Abstract

As an important component of the immunosuppressive tumor microenvironment (TME), it has been established that mesenchymal stem cells (MSCs) promote the progression of tumor cells. MSCs can directly promote the proliferation, migration, and invasion of tumor cells via cytokines and chemokines, as well as promote tumor progression by regulating the functions of anti-tumor immune and immunosuppressive cells. MSCs-derived extracellular vesicles (MSCs-EVs) contain part of the plasma membrane and signaling factors from MSCs; therefore, they display similar effects on tumors in the immunosuppressive TME. The tumor-promoting role of macrophage migration inhibitory factor (MIF) in the immunosuppressive TME has also been revealed. Interestingly, MIF exerts similar effects to those of MSCs in the immunosuppressive TME. In this review, we summarized the main effects and related mechanisms of tumor-associated MSCs (TA-MSCs), TA-MSCs-EVs, and MIF on tumors, and described their relationships. On this basis, we hypothesized that TA-MSCs-EVs, the MIF axis, and TA-MSCs form a positive feedback loop with tumor cells, influencing the occurrence and development of tumors. The functions of these three factors in the TME may undergo dynamic changes with tumor growth and continuously affect tumor development. This provides a new idea for the targeted treatment of tumors with EVs carrying MIF inhibitors.

Keywords: Anti-tumor immune cells; Extracellular vesicles; Immunosuppressive cells; Immunosuppressive tumor microenvironment; Macrophage migration inhibitory factor; TA-MSCs.

Fig. 1

A TA-MSCs promote immunosuppressive cells by secreting EVs and cytokines to indirectly promote tumor progression. B TA-MSCs inhibit anti-tumor immune cells by secreting EVs and cytokines to indirectly promote tumor progression. C TA-MSCs directly promote tumor progression by promoting tumor cells proliferation, migration, invasion. EMT and drug resistance, and inhibiting apoptosis. D TA-MSCs indirectly promote tumor progression by promoting tumor stem cells formation, tumor angiogenesis, fusion with tumor cells and spontaneous malignant transformation

Fig. 2

A MIF indirectly promotes tumor progression by promoting immunosuppressive cells. B MIF indirectly promotes tumor progression by inhibiting anti-tumor immune cells. C MIF directly promote tumor progression by promoting tumor cells proliferation, migration, invasion, EMT and drug resistance, and inhibiting apoptosis

Fig. 3

A Highly expressed MIF in tumors and stroma induce MSCs homing to TME. B After homing to tumor, MSCs are subsequently educated by tumor cells and TME to transform into TA-MSCs. C TA-MSCs-EVs promote the proliferation, migration and invasion of tumor cells through MIF transport, thus promoting tumor progression. D High levels of MIF in TME protect TA-MSCs from senescence and apoptosis