Tumor-Derived Extracellular Vesicles: Their Role in Immune Cells and Immunotherapy

Figures & data

Figure 1 Effects of TEVs on immune cells. TEVs can directly or indirectly inhibit the functions of immune cells (T cell, B cell, DC, macrophages and NK cell) through a variety of ways, and help tumor escape immune surveillance and clearance, thereby promoting tumor occurrence, growth and metastasis.

Table 1 The Inhibitory Effect of TEVs on Immune Cells

Immune Cell	Effect	Impact Factor	Source of EVs	Reference
T cell	Inhibit T-cell activation	CD39, CD73	Various cancers exosomeal	[^Citation17]
		PD-L1	Glioblastoma EVs	[^Citation18]
	Inhibit T-cell proliferation	TGF-β	Breast cancer cell exosomal	[^Citation16]
	Promote T-cell apoptosis	Fas L	Ovarian cancer exosomal	[^Citation23]
	Dysfunction; inhibit Th1 and Th17 differentiation; suppress T-cell functions	miR-24-3p, miR-891a, miR-106a-5, miR-20a-5p, miR-1908	Nasopharyngeal carcinoma exosomal	[^Citation26]
		PD-L1	Melanoma/lung/breast cancer exosomal	[^Citation30]
		miR-23a-3p	Hepatocellular carcinoma cells exosomal	[^Citation29]
	Activate Tregs; promote Treg expansion	CCL20	Nasopharyngeal carcinoma exosomal	[^Citation33]
		TGF-β	Colorectal cancer cell EVs	[^Citation32]
		miR-214	Lewis lung cancer and human embryonic kidney cell line microvesicles	[^Citation34]
		miR-24-3p	Nasopharyngeal carcinoma (NPC) cell lines and patient sera exosomal	[^Citation25]
	Enhance the inhibitory effect of MDSCs on γδT cells	miR-21	Oral squamous cell carcinoma (OSCC) cell lines Cal-27 and SCC- 9 exosomal	[^Citation36]
B cell	Suppression function	Tumor antigen	Pancreatic cancer exosomal	[^Citation38]
		—	Mycoplasma infects tumor cells exosomal	[^Citation40]
	Promote Breg expansion	—	Esophageal cancer microvesicles	[^Citation39]
Macrophages	Formation of inflammatory environment before metastasis	miR-21; miR-29a	Lung cancer cell lines A549 and SK-MES exosomal	[^Citation43]
		Annexin A2, IL-6, TNF-α	Breast cancer exosomal	[^Citation44]
		GCSF, IL-6, IL-8, IL-1β, CCL2, TNF-α	Breast cancer exosomal	[^Citation63]
	Induce the polarization of macrophage to M2 phenotype	miR-222-3p	Epithelial ovarian cancer Skov-3 cells exosomal	[^Citation48]
		—	Glioblastoma stem cell exosomal	[^Citation50]
		—	Lung cancer cell exosomal	[^Citation49]
DCs	Inhibit antigen presentation function	miR-203	Pancreatic cancer cell panc-1 exosomal	[^Citation53]
		miR-212-3p	Pancreatic cancer cell line PANC-1, SW1990, BxPC-3 exosomal	[^Citation52]
	Change the direction of differentiation	—	Breast cancer/lung cancer exosomal	[^Citation54]
		—	Melanoma/colorectal cancer exosomal	[^Citation55]
NK cell	Down-regulate the expression of the activating receptor NKG2D	MICA*008	Human cervical cancer exosomal	[^Citation58]
		NKG2Dligand	Leukemia/lymphoma exosomal	[^Citation64]
	Inhibit NK cell function; impair NK cell-mediated cytotoxicity	TGF-β	Acute myeloid leukemia exosomal	[^Citation23]
		miR-92b	Serum exosomal from rat model of orthotopic liver tumor	[^Citation61]
		miR-23a;TGF-β	Multiple tumor cells derived microvesicles	[^Citation59]

Figure 2 Application of TEVs in tumor diagnosis, drug vesicles and immunotherapy. TEVs can not only be used as a biomarkers or drug delivery vehicle due to its own advantages, but also can be used as a tumor vaccine for tumor immunotherapy.

Table 2 Clinical Trials on Using TEVs for Tumor Diagnosis Biomakers

Cancer Type	Vesicles	Sample	ID	Apply
Colorectal cancer	TEXs proteins	Blood	NCT04394572	Early diagnosis
Colorectalcancer	TEXs miRNA	Blood	NCT04523389	Early prognostic
Lung cancer	Exosomes	Blood plasma	NCT04529915	Early diagnosis
HER2-positive breast cancer	Exosomes	Blood and tumor tissue	NCT04288141	Diagnosis
Prostate cancer	Exosomes gene	Urinary	NCT02702856	Diagnosis
Clear cell renal cell carcinoma	Exosomes	Urinary	NCT04053855	Early diagnosis
Pancreatic cancer	Exosomes	Blood and tissue	NCT02393703	Diagnosis
Bladder cancer	Exosomes	Urinary	NCT04155359	Diagnosis
Lung cancer	Exosomes	Blood	NCT04629079	Early diagnosis
Prostate cancer	Exosomes	Blood	NCT04556916	Early diagnosis
Papillomavirus-positive oropharyngeal squamous cell carcinoma	Exosomes	Blood and saliva	NCT02147418	Screening
Rectal cancer	Exosomes	Blood	NCT03874559	Diagnosis
Lung cancer	TEXs IncRNA	Serum	NCT03830619	Early diagnosis
Metastatic breast cancer	Exosomes	Blood/tissues	NCT04258735	Genomic analysis
Digestive and gynecologic/breast cancer	TEXs DNA	Blood	NCT04530890	Diagnosis
Prostate cancer	Exosomes	Blood	NCT03694483	Diagnosis
Rectal cancer	TEVs	Blood	NCT04852653	Liquid biopsy
NSCLC	Exosomes	Blood	NCT04499794	Prognostic

Table 3 Study of TEVs as Drug Vehicles

Drugs	Source	Type	Delivery Methods	Targets	Effect	Reference
Paclitaxel	Prostate cancer LNCaP and PC-3 cells	Exosomes	Incubation	Autologous prostate cancer cells	Increased the anti-tumor effect of Paclitaxel	[^Citation75]
Curcumin	Pancreatic adenocarcinoma cell (PANC-1, MIA PaCa-2) derived exosomes	Exosomes	Tumors cells which treatment with drugs	PANC-1; MIA PaCa-2	Promoting anti-tumor effect reduces tumor cells viability	[^Citation77]
siRNA	Plasma exosomes	Exosomes	Electroporation	Monocytes; lymphocytes	Provide cells with heterologous nucleic acids such as therapeutic siRNAs	[^Citation72]
Paclitaxel	Glioblastoma cell line U-87	Exosomes	Incubation; sonication	U-87	Increased drugs effect against U-87 cell line	[^Citation78]
Curcumin	Mouse macrophage cell line Raw264.7	Exosomes	Electroporation	Human glioma cell line U251; human hepatoma cell line Bel-7404	Provided good results for targeted imaging and therapy of glioma.	[^Citation76]

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