Tumor-derived extracellular vesicles modulate innate immune responses to affect tumor progression

Abstract

Immune cells are capable of influencing tumor progression in the tumor microenvironment (TME). Meanwhile, one mechanism by which tumor modulate immune cells function is through extracellular vesicles (EVs), which are cell-derived extracellular membrane vesicles. EVs can act as mediators of intercellular communication and can deliver nucleic acids, proteins, lipids, and other signaling molecules between cells. In recent years, studies have found that EVs play a crucial role in the communication between tumor cells and immune cells. Innate immunity is the first-line response of the immune system against tumor progression. Therefore, tumor cell-derived EVs (TDEVs) which modulate the functional change of innate immune cells serve important functions in the context of tumor progression. Emerging evidence has shown that TDEVs dually enhance or suppress innate immunity through various pathways. This review aims to summarize the influence of TDEVs on macrophages, dendritic cells, neutrophils, and natural killer cells. We also summarize their further effects on the progression of tumors, which may provide new ideas for developing novel tumor therapies targeting EVs.

Keywords: dendritic cells; macrophages; natural killer cells; neutrophils; tumor progression; tumor-derived extracellular vesicles (TDEVs).

Figure 1

Schematic model of TDEVs in regulating the functions of macrophage. TDEVs can modulate the cytokine secretion, phagocytosis, and migration of macrophages via various signaling pathways. For cytokine secretion (Blue): Palmitoylated proteins carried by gastric cancer-derived EVs bind with TLR2 on the surface of macrophages to further activate NF-κB signaling, leading to an elevated level of pro-inflammatory cytokines including IL-6, IL-1β, TNF-α and so on. Similarly, miRNAs in EVs secreted by lung cancer and breast cancer bind with TLR7/8 to induce pro-inflammatory cytokines secretion via the NF-κB pathway. However, HNSCC-derived EVs cargo TGF-β isoform inhibits NF-κB signaling to down-regulate the expression of pro-inflammatory cytokines. For phagocytosis (Green): PtdSer in apoptotic tumor-derived EVs binds with receptors such as TIM-4 to promote the phagocytosis of apoptotic cells by macrophages. However, lncRNA TUC399 contained in HCC-derived EVs down-regulates the FcγR-mediated phagocytosis. For migration (Red): TDEVs from myeloma containing serglycin can augment macrophage migration, and SIPA1 in breast cancer-derived EVs induces elevated expression of myosin-9 in macrophages, which contributes to migration.

Figure 2

Effects of TDEVs in regulating DCs, neutrophils, and NK cell functions. TDEVs can interact with innate immune cells including DCs, neutrophils, and NK cells, exerting a dual effect in regulating their functions. TDEVs to DCs: EVs containing tumor antigen from HCC can transfer it to DCs and further activate T cell immunity, indicating its anti-tumor effect. TDEVs can impair DCs differentiation and maturation to suppress immune responses in some cancers, HLA-G is identified as a key factor in this negative regulation. Some TDEVs contain HSP72 and HSP105 bind with TLR on DCs to increase MMP9 expression, reorganizing ECM and contributing to tumor invasion. TDEVs to neutrophils: circRNA PACRGL in CRC-derived EVs are engulfed by neutrophils and down-regulate TGF-β1 expression, further inducing polarization to the N2 phenotype. TDEVs can also induce NET formation by neutrophils in a dose-dependent way, which further contributes to thrombosis. TDEVs containing HMGB1 can upregulate PD-L1 on neutrophils to suppress T cell immunity, exerting a pro-tumor effect. TDEVs to NK cells: BAG6/BAT3 on the surface of TDEVs can bind with NKp30 to suppress NK cytotoxicity via the nSmase2-dependent pathway. NKG2DLs, TGF-β, and other immunosuppressive proteins from TDEVs bind with NKG2Ds on the surface of NK cells to block NK cytotoxicity.