Exosomes inhibit tumor progression
In the tumor microenvironment, exosomes may mediate intracellular communication and immune regulation. Tumor-derived exosomes (TEXs) and immune cell-derived exosomes (IEXs) have been demonstrated to activate immune responses by transferring antigens to antigen presenting cells (APCs), which results in the activation of CD4
+ T cells and CD8
+ T cells, thereby enhancing the anti-tumor responses and leading to the inhibition of tumor progression [
17]. Additionally, an alternative mode of action has also been described that involves inducing the apoptosis of tumor cells [
18]. The latest research has found that TEXs and IEXs could be applied to oncotherapy as monitoring markers instead of detecting T lymphocytes and taking tumor biopsies [
19]. In the following description, we introduce the anti-tumor effect of TEXs and IEXs. (Tables
1 and
2).
Table 1
The regulatory role of tumor cell-derived exosomes in tumor progression
Heat-stressed tumor cell | ↑ | | ↓ | ↑ | | | | ↓ | |
Hepatocellular carcinoma cell | ↑ | ↑↓ | | | ↑ | ↓ | | ↑↓ | |
Malignant glioma cell | ↑ | ↑ | | | | | | ↓ | |
Leukemia cell | ↑ | ↑ | | | | ↑ | | ↓ | |
RenCa cell | | ↑ | | | | | | ↓ | |
Gastric cancer cell | | ↓ | | | | | ↑ | ↑ | |
Melanoma cell | | ↓ | | | | | | ↑ | |
Table 2
The regulatory role of immune cell-derived exosomes in tumor progression
DC | | ↑ | ↑ | ↓ | | ↓ | |
CD4+ T cell | | | ↓ | | | ↑ | |
CD8+ T cell | ↓ | | ↑ | | | ↑↓ | |
Macrophage | | ↑ | | | | ↓ | |
TAM | ↓ | | | ↑ | ↑ | ↑ | |
Mast cell | ↑ | ↑ | ↑ | | | ↓ | |
B cell | ↑ | ↑ | ↓↑ | | | ↓↑ | |
MDSC | | | ↓ | | | ↑ | |
Treg | | | ↓ | | | ↑ | |
Considering the origin of exosomes, TEXs may contain some tumor-associated antigens, including melan A, carcinoembryonic antigen and mesothelin [
39,
40]. Thus, TEXs could be used to form a pool of tumor antigens to stimulate the anti-tumor response. Currently, TEXs have been widely used for the induction of anti-tumor responses in both murine models and clinical trials. A recent study reported that exosomes derived from heat-stressed tumor cells could induce the production of IL-6 by DCs and marcophage, which switches regulatory T cell into Th17 in tumor microenviroment in a HSP-70 dependent manner [
20]. DCs have been proven to be a target for TEXs to enhance anti-tumor responses [
21]. Research has found that EG7 tumor cell-derived exosomes transfer parental cell-associated antigen OVA and pMHC-I to DCs, which stimulate a stronger proliferation and differentiation of cytotoxic T lymphocytes (CTL) and generating a more robust OVA-specific antitumor immunity than control ones. Similar results were obtained in hepatocellular carcinoma (HCC) models and in other studies [
21,
22]. Simultaneously, exosomes from TGF-β-silenced leukemia cells decrease the secretion of TGF-β by DCs and effectively promote their maturation and function. Additionally, DCs carrying these exosomes facilitated the proliferation of CD4
+ T cells and enhanced the antigen-specific CTL responses [
26,
27]. Interestingly, TEXs which exert a stable antitumor response are mostly based on targeting DCs. These provide a new idea for our future research.
It has been reported that IEXs also contribute to enhancing the anti-tumor response. In addition, IEXs could alter the microenvironment suitable for tumors to suppress tumor growth. Recently, DC-derived exosomes (DEXs) have been recognized as a new class of vaccines for tumor therapy [
35,
41]. In this research, Lu and coworkers found that exosomes derived from a-fetoprotein (AFP)-expressing DCs could promote the antigen-specific immune response through elevating the levels of IFN-γ and interleukin-2 and reducing the expression of interleukin-10 and TGF-β. Activated CD8
+ T cell-derived extracellular vesicles are able to directly target mesenchymal tumor stromal cells to prevent tumor invasion and metastasis [
34]. Exosomes released by NK cells have also been identified as having therapeutic effects. Both in vitro and in vivo experiments revealed that NK cell-derived exosomes could suppress the development of melanoma via their contents of TNF-α, perforin and FasL [
42]. In neuroblastoma (NB) tumors, exosomes derived from NK cells pretreated with NB cells increased the expression of natural killer cell receptors and enhanced the cytotoxicity of NK cells against NB tumors [
43].
In addition to the exosomes mentioned above, exosomes derived from mesenchymal stem cells (MSCs) have also been reported to restrain tumor development [
44]. MSC-derived exosomes have potent regulatory effects on immune responses involving different immune cells, such as T cells and B cells [
45]. Researchers have demonstrated that human adipose MSC-derived exosomes inhibit the proliferation and colony formation ability of A2780 and SKOV-3 human ovarian cancer cells via inducing the expression of BAX and CASP3/9 while reducing the levels of BCL2 [
46]. Interestingly, researchers have obtained similar results from human umbilical cord MSC-derived extracellular vesicles (EVs) [
47].
Despite exosomes having anti-tumor effects as mentioned above, more studies have focused on their effects in promoting tumor progression [
48]. The growth of tumor is associated with various growth factor receptors and signaling pathways. These receptors triggers downstream signaling pathways via Akt, PKC/PKB and ERK kinase pathways through the activation or phosphorylation of intracellular kinase domain which leads to tumor cell proliferation and migration.
In NB tumors, TEXs promote tumor proliferation and migration by decreasing the expression of NEDD4 by hsa-miR199a-3p [
49]. TEXs derived from the Lewis lung cancer model and 4 T1 breast cancer model inhibit the differentiation of myeloid precursors into DCs and their maturation by increasing the expression of immunosuppressive markers PD-L1 to trigger inhibitor signals [
50]. Moreover, studies have reported that gastric cancer-derived exosomes can induce monocytes to differentiate into PD-1
+ tumor-associated macrophages (TAMs), which can effectively suppress anti-tumor responses by triggering the PD-1/PD-Ls signaling pathway [
51]. Exosomes derived from oral squamous cell carcinoma could upregulate the expression of PD-L1 on myeloid-derived suppressor cells (MDSCs) to induce ɣδ T cell exhaustion through an exosome miR-21/PTEN/PD-L1 pathway [
52]. Similar results have been obtained in hepatocellular carcinoma (HCC) cells. Liu J and colleagues discovered that exosomes released from HCC cells upregulated the expression of PD-L1 in macrophages to inhibit T-cell function through a miR-23a/PTEN/AKT regulation axis [
53]. In addition, exosomes obtained from melatonin-treated hepatocellular carcinoma cells were able to downregulate the expression of PD-L1 and the secretion of cytokines (IL-6, IL-1β, IL-10, and TNF-α) in macrophages [
54]. In light of this, we surmise that miRNAs contained in tumor-derived exosomes may facilitate the growth and metastasis of tumors [
55].
IEXs and exosomes secreted by other cells have also been reported to facilitate the growth and metastasis of tumors. Exosomes derived from activated CD8
+ T cells can promote the invasion of tumor cells via the Fas/FasL pathway [
7]. However, another study has shown that activated T cell-derived exosomes promote tumor invasion and metastasis through the ERK and NF-κB pathways. Exosomes released by activated OVA-specific CD4
+ T cells can suppress the cytotoxicity of DC-stimulated CD8
+ T cells via pMHC II/TCR and CD54/LFA-1 interactions. Recently, a study described the functions of EVs derived from B cells in anti-tumor responses [
36]. CD39
+CD73
+ EVs released by tumor B cells hydrolyze ATP and AMP from tumor cells into adenosine to inhibit the proliferation of CD8
+ T cells. In a clinical trial, higher CD19
+ EVs in tumor patients’ serum were associated with poor efficacy of chemotherapy. These results indicate that exosomes may not have the characteristics of the parent cells [
33]. In osteosarcoma and gastric cancer patients, researchers have found that human bone marrow MSC-derived exosomes (MSC-exo) could promote tumor progression through the activation of the Hedgehog signaling pathway [
56]. Our data shown that exosomal S100A9 from granulocytic myeloid-derived suppressor cells promotes CRC cell stemness and growth [
9].
Whether pro-tumor or anti-tumor function of TEXs and IEXs, these researches state the importance of them in tumor progression and define emergence of new paradigms in tumor cell biology. In terms of tumor inhibition, IEXs exert anti-tumor response primarily through their contents, such as TNF-α, perforin, FasL and so forth. However, TEXs activate the anti-tumor immune response mainly by presenting tumor antigens to DCs. In terms of tumor promotion, the molecules expressed on IEXs, such as FasL and pMHC II, interact with T cells to trigger co-inhibitor signals and promote apoptosis. TEXs have the similar effect as IEXs. The contents contained in TEXs have the ability to up-regulate the expression of PD-L1 on myeloid cells to inhibit the function of T cells through PD-1/PD-L1 signaling pathway. And exosomal MHC I could promote this inhibit function by inducing the first signal activation of T cells. Recent studies have demonstrated that exosomes can carry PD-L1 on their surface and have been proven to play a key role in tumor development [
57‐
59]. Because of their remarkable immunosuppressive function, exosomes may be a cancer therapy target in the future.