The role of tumor derived macrophages in the anti-tumor effects of MEK1-hi exosomes

Exosomes are cell-secreted, nanometer-sized vesicles that can carry proteins as bioactive cargo. In the tumor microenvironment, cancer cell-derived exosomes have been shown to promote a target cell phenotype that is either immune activated or suppressed. The immunomodulatory effects of cancer cell exosomes have therefore driven their potential as both disease biomarkers and promising cancer immunotherapies. Previously, exosomes containing high levels of MEK1 protein were shown to mediate tumor regression compared to control exosomes containing low levels of MEK1. To understand the immunological mechanism by which MEK1-hi exosomes induce tumor regression, we studied the gene expression of tumor-derived (TD) macrophages treated with MEK1-hi vs MEK1-lo exosomes in vitro and in vivo. We found that treating TD macrophages with MEK1-hi exosomes in vitro significantly induced chemokine ligand 2 and chemokine ligand 7 (Ccl2 and Ccl7). Additionally, TD macrophages from an MEK1-hi tumor upregulated a set of interferon gamma (IFNγ) response genes. Finally, when MEK1-hi tumor cells were used to establish tumors in mice, only tumor-bearing mice injected with IgG and not anti-IFNγ blocking antibody showed significant size regression in the days post tumor establishment. These findings suggest that MEK1-hi exosomes recruit an anti-tumor immune response through IFNγ, which is functionally required to induce tumor regression. We conclude that tumor macrophages can take up MEK1-hi exosomes and secrete pro-inflammatory chemokines that presumably recruit and prime NK cells to produce IFNγ, leading to tumor regression