Table 1.
Archetypal NK receptors in NK cell function, exhaustion and restoration.
| NK cell Receptors | Activating/Inhibitory | Status/Modification | Context | Ref |
|---|---|---|---|---|
| NKG2A | Inhibitory | Upregulated | Increased expression in intratumour Hepatocellular Carcinoma (HCC) tissues from human patients, correlating with poor prognosis and functional exhaustion Increased expression in peripheral and tumour-associated NK cells in breast cancer patients |
(10, 21) |
| Antibody blockade | Phase II clinical trial – in combination with cetuximab, increased NK cell killing by antibody-dependent cellular cytotoxicity (ADCC) in patients with squamous cell carcinoma of head and neck | (22) | ||
| PD-1 | Inhibitory | Upregulated | Increased expression on NK cells from myeloma patients (reportedly no expression on healthy donor NK cells) Increased expression on both peripheral and tumour-infiltrating NK cells from patients with digestive cancers. Poor prognosis in liver and esophageal cancers. |
(23, 24) |
| Antibody blockade | Expanded NK cells from healthy donor peripheral blood – increased cytotoxicity against multiple myeloma cell lines, human and murine model of Multiple Myeloma (MM) Mouse model of lymphoma – blocking antibody against PD-1 reduced tumour progression |
(24–26) | ||
| TIGIT | Inhibitory | Upregulated | Increased expression on intratumoral NK cells from soft tissue sarcoma, colon and endometrial cancer patients | (27–29) |
| Downregulated | Decreased expression on tumour-infiltrating NK cells from melanoma patients | (30) | ||
| Antibody blockadea | Primary NK cells from sarcoma patients – increased degranulation and cytotoxicity against sarcoma cell lines Peripheral NK cells from melanoma patients – increased cytotoxicity against melanoma cell line and increased IFNγ production Mouse models of various cancers: colon, breast, fibrosarcomas – reduced tumour volume, increased CD107, TNF and IFNγ expression |
(27, 28, 30) | ||
| TIM-3 | Inhibitory | Upregulated | Increased expression on peripheral NK cells from melanoma and bladder cancer patients, corresponding with poor prognosis. Increased expression on intratumoral NK cells from endometrial and bladder cancer patients |
(29, 31, 32) |
| Downregulated | Decreased expression on healthy human NK cells upon exposure to glioblastoma cell lines, corresponding with decreased cytotoxicity and IFNγ production. | (33) | ||
| Antibody blockade | Primary NK cells from melanoma patients and healthy donor NK cells – increased NK cell cytotoxicity against four melanoma cell lines | (31) | ||
| DNAM-1 | Activating | Downregulated | Decreased expression on tumour-associated NK cells from breast and ovarian carcinoma patients Decreased expression on peripheral and tumour-associated NK cells in gastric and breast cancer patients |
(10, 34, 35) |
| Overexpression | NK-92 cell line – increased degranulation against primary sarcoma and various other cancer cell lines | (36) | ||
| NKG2D | Activating | Downregulated | Decreased expression on tumour-infiltrating NK cells in breast cancer and melanoma patients. Decreased expression on peripheral NK cells from melanoma, breast and gastric cancer patients. |
(10, 30, 31, 35) |
| Overexpression | NK-92 cell line – increased degranulation against primary sarcoma and various other cancer cell lines Primary NK cells from metastatic melanoma patients – enhanced NK cell cytotoxicity in vitro against target K562 cells |
(36, 37) | ||
| NKp30 | Activating | Downregulated | Decreased expression on peripheral NK cells from breast and gastric cancer patients and associated with cancer progression Decreased expression on tumour-associated NK cells from breast cancer patients |
(10, 35) |
| NKp44 | Activatingb | Antibody blockade | NK-92 cell line in vitro – increased cytotoxic activity and IFNγ release against solid tumour and leukemia cell lines NK-92 and HNSCC patient autologous NK cells in PDX-bearing mice – increased degranulation and inhibited tumour growth |
(38) |
| NKp46 | Activating | Downregulated | Decreased expression on peripheral NK cells from gastric cancer patients and associated with cancer progression Decreased expression on peripheral NK cells from melanoma patients. |
(31, 35) |
| Overexpression | Mouse model of melanoma – increased NK cytotoxicity and tumour clearance | (39) |
aTIGIT blockade alone increases IFNγ production in circulating NK cells, but has to be used in combination with IL-15 to promote increased cytotoxicity in tumour infiltrating NK cells (30).
bNKp44 is classified as an activating receptor, but can also have inhibitory effects when engaged with inhibitory ligands such as PCNA (40).