Table 1.
Cytokines and chemokines involved in the NK-myeloid cell crosstalk and drugs directed to modulate these interactions.
| A. Myeloid cell-derived cytokines and their effects on NK cells. | |||||
|---|---|---|---|---|---|
| Cytokine | Produced by | Effects | Therapy | Ref. | |
| TGF-β | MDSCs, TAMs, tumor cells, mast cells | ↓activating receptor, cytokine production, cytotoxicity, proliferation | Fresolimumab, galunisertib, M7824 (clinical trial) | (25–30) | |
| IL-10 | MDSCs, TAMs, NK cells, DCs, macrophages | ↓/↑ cytotoxicity, cytokine production | – | (24, 31–33) | |
| IL-32α | DCs | ↓perforin, granzyme B | – | (34) | |
| TNF | Macrophages | ↑ cytokine production | – | (35) | |
| IL-12 | DCs, macrophages, monocytes, neutrophils | ↑ cytotoxicity, cytokine production, proliferation, survival | IL-12, IL-12 + pembrolizumab (clinical trial) | (21, 36) | |
| IL-15 | DCs, macrophages, monocytes | ↑ cytotoxicity, cytokine production, proliferation, survival, activating receptors, KIR | ALT-803 (phase 1 and 2 clinical trial), IL-15 + Ipilimumab and Nivolumab (phase 1 clinical trial) | (37–39) | |
| IL-18 | M0 macrophages, TAMs, DCs, | ↑ cytotoxicity, cytokine production, proliferation, survival | IL-18 (phase 1 and 2 clinical trial) | (40–44) | |
| IL-21 | DCs | ↑ cytotoxicity, proliferation, activating receptors | IL-21, IL-21 + Ipilimumab and nivolumab (phase-I and –II clinical trial) | (45) | |
| IL-6 | MDSC, TAM, tumor cell, macrophages, monocytes, mast cells | ↓/↑ cytotoxicity, ↓ cytokine production | Tocilizumab (clinical trial) | (46, 47) | |
| IL-1α | Monocytes, DCs, macrophages | ↓maturation | Anakinra, Canakinumab, Isunakinra (phase 1 and 2 clinical trial) | (23) | |
| IL-27 | DCs, macrophages, MDSCs | ↓/↑ cytotoxicity, cytokine production | p28 peptide | (48–53) | |
| IL-23 | MDSC and TAM, DC and macrophage | ↓/↑ cytotoxicity, cytokine production | – | (54, 55) | |
| IL-17 | Neutrophils | ↑cytotoxicity, ↓maturation | – | (56, 57) | |
| IFN-α/β | DC | ↑ cytotoxicity, cytokine production, proliferation, survival, NKG2D | IFN-α/β approved | (58) | |
| B. NK cell-derived cytokines and their effects on myeloid cells. | |||||
| Cytokine | Target population | Effects | Therapy | Ref. | |
| IFN-γ | DCs | maturation, activation | – | (59–61) | |
| TAMs | polarization towards pro-inflammatory Mφ | – | (62, 63) | ||
| TANs | inhibition of pro-tumorigenic TANs | – | (64) | ||
| TNF-α | DCs | maturation, activation | – | (59–61) | |
| TAMs | polarization towards pro-inflammatory Mφ | – | (62) | ||
| HMGB1 | DCs | activation | – | (43, 65) | |
| GM-CSF | DCs | activation | – | (62) | |
| TAMs | polarization towards pro-inflammatory Mφ | – | (62) | ||
| TANs | activation, promotes NETs | – | (66–68) | ||
| VEGF-A | Endothelial cells, tumor cells | proliferation, migration | – | (69) | |
A) Effects of myeloid cell-derived cytokines on NK cells and therapeutic targeting thereof. B) Effects of NK cell-derived cytokines on the maturation and differentiation of different myeloid cell subsets and therapeutic targeting thereof.