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Engineering exosomes to contain MEK1 as cancer immunotherapy


Exosome-mediated transfer of bioactive cargo among cells is now appreciated as a bonafide method of intercellular communication. In cancer, exosomes have been understood mostly as tumor-promoting factors that are secreted abundantly to promote cell proliferation of non-transformed cells, inhibit anti-tumor immune responses, and facilitate metastasis.

Using mouse progressor and regressor cell lines as a model system, we have identified an immune-stimulating activity of exosomes derived from regressor tumor cells. Our proteomic data revealed that only exosomes from regressor cells contained the protein MAP kinase kinase 1 or MEK1. Notably, simply overexpressing this protein in progressor cells can engineer exosomes to carry MEK1 proteins. These MEK1-containing exosomes can be used therapeutically to induce tumor rejection, which requires the immune system and correlates with an increase in natural killer (NK) cells and M1-type macrophages and a decrease in M2-type macrophages in the tumor. While exosomes have been shown to be taken up by macrophages, their anti-tumor effects are independent of patrolling monocytes, thereby suggesting that exosomes exert their activity in tumor macrophages or classical blood monocytes. Indeed, we have found that exosome treatment of both bone marrow-derived and tumor-derived macrophages can induce the activation of both M1 and M2 genes.

To translate these findings, generating human exosomes with abundant expression of MEK1 is required. Other groups have shown that human telomerase immortalized-mesenchymal stem cells, or hTERT-MSCs, could be engineered to overexpress various genes. hTERT-MSCs have also been approved by the Food and Drug Administration (FDA) for use in patients, so generating exosomes from these cells could lead to a therapeutic reagent that could receive rapid FDA approval. As proof-of-principle, MEK1 was transduced into hTERT-MSCs and shown to be overexpressed in the cytoplasm. Future studies will test exosomes from these human cells and examine the activation of human blood monocytes by human MEK1-containing exosomes.

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