Xenogenization by fusogenic exosomes in tumor microenvironment ignites and propagates antitumor immunity

Many cancer patients not responding to current immunotherapies fail to produce tumor-specific T cells for various reasons, such as a lack of recognition of cancer cells as foreign. Here, Korea University researchers suggest a previously unidentified method for xenogenizing (turning self to non-self) tumors by using fusogenic exosomes to introduce fusogenic viral antigens (VSV-G) onto the tumor cell surface. The researchers found that xenogenized tumor cells were readily recognized and engulfed by dendritic cells; thereby, tumor antigens were efficiently presented to T lymphocytes. Moreover, exosome–VSV-G itself acts as a TLR4 agonist and stimulates the maturation of dendritic cells, leading to CD8+ T cell cross-priming. The administration of these exosomes in multiple tumor mouse models xenogenized tumor cells, resulting in tumor growth inhibition. The combinatorial treatment with anti–PD-L1 exhibited complete tumor regression (30%) and better long-term overall survival. These results suggest that tumor xenogenization by fusogenic exosomes provides a previously unidentified novel strategy for cancer immunotherapy.

Schematic illustration of mVSVG-Exo–mediated tumor xenogenization strategy

(A) mVSVG-Exo fuses with the tumor cell membrane in an LDLR- and pH-dependent manner. (B) mVSVG-edited tumor cells are more easily engulfed by phagocytes. (C) mVSVG-Exo can activate DC functions by stimulating TLR4 signaling. This strategy enhances cross-prime ability, which can further increase CD8+ T cell immunity against cancer.

Kim GB, Nam GH, Hong Y, Woo J, Cho Y, Kwon IC, Yang Y, Kim IS. (2020) Xenogenization of tumor cells by fusogenic exosomes in tumor microenvironment ignites and propagates antitumor immunity. Science Advances 6(27); eaaz2083. [article]

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