Table 1.
Immunomodulatory function of EVs containing purinergic enzymes, receptors and metabolites.
| Purinergic molecule | Cell type | Source | Function | References |
|---|---|---|---|---|
| CD73 | Cancer cells | Human HNSCC cells | Immunosuppressive; tumor-associated macrophages phagocytose HNSCC-derived CD73+ EVs promoting tumor immunosuppression, M2 polarization and higher immune checkpoint expression in vivo | (27) |
| Human and murine glioblastoma cells | Immunosuppressive; T cells take up glioblastoma-derived CD73+ EVs, which prevent their expansion, promoting tumor growth in vivo, A2A receptor-dependent | (28) | ||
| Ovarian cancer-, colon cancer-, non-small cell lung carcinoma cells | Anti-CD73 antibodies revoke adenosine-mediated immune suppression by tumor-derived EVs in vitro | (29) | ||
| Serum of patients with melanoma | Immunosuppressive; CD73+ EVs suppress T cell function in vitro | (30) | ||
| Immune cells | Activated human peripheral CD8+ T cells | Immunosuppressive; CD8 T cell-derived CD73+ EVs suppress T cell proliferation and cytokine production in vitro | (31) | |
| Activated murine Tregs | Immunosuppressive; adenosine production by Treg-derived CD73+ EVs contributes to Treg-mediated suppressive activity in vitro | (26) | ||
| Low-dose IL-2 treatment induced murine Tregs | Immunosuppressive; FoxP3+ CD73+ EVs delay chronic cardiac allograft rejection in vivo | (32) | ||
| Mesenchymal stem cells | Human umbilical cord MSC | Immunosuppressive; adenosine production by MSC-derived EVs in cooperation with activated T cells in vitro | (33) | |
| Human bone marrow MSC | Induction of immune tolerance in vivo in a xenogeneic GvHD model by adenosine production | (34) | ||
| Cytokine-stimulated human gingival MSC | Immunosuppressive; EVs enhance M2 macrophage polarization in vitro, CD73-dependent | (35, 36) | ||
| Human MSC cell line | M2 macrophage polarization in vitro, CD73- and adenosine-dependent | (37) | ||
| Human bone marrow MSCs | CD73 enzymatic activity of MSC EVs does not correlate with their immunomodulatory potential in vitro | (38) | ||
| CD39 | Immune cells | Activated human peripheral Tregs | Immunosuppressive; inhibition of effector T cell proliferation, modulatory effect on cytokine profile, protective in vivo in GvHD | (39) |
| Cancer cells | Human NSCLC cell lines and primary tumor cells | Immunosuppressive; ATP degradation in CD4 T cells, affecting T cell differentiation in vitro | (40) | |
| CD39, CD73 | Cancer cells | Human bladder-, colorectal-, prostate- and breast cancer cell line, mesothelioma cell line, pleural fluid from patients with malignant pleural mesothelioma | Immunosuppressive; T cell suppression by tumor-derived CD39+ CD73+ EVs in vitro through adenosine production | (25) |
| Plasma of AML patients | Immunosuppressive; adenosine production, inhibition of NK-92 cell proliferation, cytotoxicity, migration and modulation of cytokine expression | (41) | ||
| Human plasma of patients with HNSCC | Adenosine production | (42) | ||
| Glioblastoma cell lines | Immunosuppressive in vitro | (43) | ||
| Rat glioma cell line | Anti-proliferative effect on tumor cells, leading to reduction of tumor size in vivo | (44) | ||
| Immune cells | Human and mouse B cells, human serum of colon cancer patients | Immunosuppressive; impairment of anti-tumor CD8 T cell responses by adenosine production in vivo | (45) | |
| Stem cells | Human amniotic fluids of 16-17 week pregnant women | Immunosuppressive; intrinsic ATP production and degradation to adenosine, suppression of inflammasome activation in THP-1 cells, A2A receptor-dependent | (46) | |
| CD39, CD73, Adenosine | Human plasma of HNSCC patients, HPV(+) HNSCC cell line | Adenosine production, M2 macrophage polarization in vitro, A2B receptor-dependent | (47) | |
| CD39, CD73, CD26, ADA | Human plasma of HNSCC patients | Adenosine production, active purinergic enzymes, increased expression in patients with late stage-HNSCC | (48) | |
| CD39 CD73, CD38, ENPP1 | Human bone marrow plasma of patients with multiple myeloma | Adenosine production, increased expression in patients with multiple myeloma than in controls | (49) | |
| Human bone marrow plasma of patients with neuroblastoma | Immunosuppressive; adenosine production and suppression of T cell proliferation in vitro, increased expression in patients with worse prognosis | (50) | ||
| CD39 and other NTPDases | Human plasma | ADPase activity | (51) | |
| P2X7 | Immune cells | Human Bz-ATP-stimulated DCs | P2X7-dependent lysis of the vesicles and release of pro-inflammatory cytokines | (52) |
| Adenosine | Tumor cells | Human breast cancer cell line | Immunosuppressive; inhibition of cytotoxic T cell effector function in vitro | (21) |
| Adenosine, AMP | Tumor cells | Human HNSCC cell lines, plasma of patients with HNSCC | Changes in EV-contained purine metabolites correlate with tumor progression | (22) |
| ATP | Tumor microenvironment | Murine melanoma and colon carcinoma tumors | Release of ATP-loaded microparticles and naked mitochondria upon nutrient deprivation | (23) |
AML, acute myeloid leukemia; DC, Dendritic cell, GvHD, graft vs. host disease; HNSCC, head and neck squamous cell carcinoma; M2, M2 macrophage; MSC, mesenchymal stem cell; NSCLC, non-small-cell lung cancer.