Exosomal MEK1 delays tumor growth by promoting anti-tumor immunity

Abstract

Abstract Exosomes mediate intercellular communication and regulation in many processes, including cancer-immune cell interactions. Exosomes are small (~100 nm) membrane vesicles that arise from the late endosomal pathway and contain bioactive molecules that are transferred to and affect the function of target cells. Tumor-derived exosomes are important regulators of anti-tumor immunity and have been shown to exert stimulatory and inhibitory effects on immune cells, depending on the experimental setting. Using a proteomic approach, we found that exosomes derived from tumors that undergo immune rejection (“regressors”) contain different proteins than exosomes from progressively growing tumors (“progressors”). Specifically, the signaling molecule MAP2K1 (“MEK1”) is highly enriched in regressor compared to progressor exosomes, leading us to hypothesize that exosomal MEK1 stimulates anti-tumor immunity and inhibits tumor progression. We found that forced expression of MEK1 in progressor exosomes delays tumor growth and increases anti-tumor immune cell infiltration, and that MEK1-hi exosomes are sufficient to delay tumor growth, but MEK1-low exosomes are not. Moreover, we found that MEK1 protein can be physically transferred from tumor cells to macrophages via exosomes, and that MEK1-hi exosomes induce pro-inflammatory cytokine production in macrophages, but MEK1-low exosomes do not. We propose that tumor-derived MEK1 is transferred to macrophages via exosomes, which enhances their anti-tumoricidal effector function and delays tumor growth. This cell extrinsic, anti-tumor activity of MEK1 contrasts with the known oncogenic properties of MEK1 and could limit the efficacy of MEK1 inhibitors currently in clinical trials.