Table 1.
Study characteristics. (Studies conducted on multiple cancer tissue sites were separated into respective cancer categories).
| Study | Year | Period of Sample Collection | Cancer Type | Cancer Subtype | n | Sex Ratio (F:M) | Age (Mean (Range)) | NK cell Marker (clone) | Stratification | NK Cell Number | HR of Death (95% CI, p-value), multivariate analysis | Impact on survival High NK cell population |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cho et al.34 | 2003 | 1989 – 1999 | Head & Neck Cancer | Esophageal squamous cell carcinoma | 122 | 17:105 | 62.3 (NR) | CD57 (Leu 7) | Quantified in the stroma into 4 groups: • most abundant • abundant • moderate • scanty |
Median = 0.9NK cells/ HPF | NR | No change, OS (p = 0.47) |
| Fang et al.35 | 2017 | 2007 – 2009 | Head & Neck Cancer | Oral squamous cell carcinoma | 78 | 21:57 | 60 (24–82) | CD57 (ab82749) | Mean NK cell number: • 〈 15.75 NK cells • 〉 15.75 NK cells |
Median = 15.75 cells/ HPF | NR | Improved, OS (p < 0.001) |
| Hsia et al.36 | 2005 | 1994 – 1996 | Head & Neck Cancer | Esophageal squamous cell carcinoma | 38 | 0:38 | NR | CD57 (NR) | Median NK cell number: • 〈 25 NK cells/ 25 fields • 〉 25 NK cells/ 25 fields |
Median = 25 cells/ 25 fields | 0.61 (0.21 – 1.82, p = 0.378) | Improved, OS (p = 0.007) |
| Lazaris et al.37 | 2007 | NR | Head & Neck Cancer | Laryngeal carcinoma | 31 | 1:30 | 61.3 (42–75) | CD56 (T119), CD16 (VIFcRII) | Quantified in the parenchyma: • low, <5% of lymphocytes • intermediate, 5–20% • high, >20% |
NR | NR | No change, DFS (p = 0.66) |
| Lu et al.38 | 2017 | 2002 – 2003 | Head & Neck Cancer | Nasopharyngeal carcinoma | 197 | 51:146 | 45.22 (NR) | CD56 (NR) | Median NK cell number | NR | 0.46 (0.27 – 0.77, p = 0.004) | Improved, OS (p – 0.001) |
| Lv et al.39 | 2011 | 2002 – 2003 | Head & Neck Cancer | Esophageal squamous cell carcinoma | 181 | 40:141 | 56 (33–79) | CD57 (NR) | Median NK cell number | NR | NR | Improved, OS (p = 0.002) |
| Schoenfeld et al.40 | 2017 | 2004 – 2013 | Head & Neck Cancer | Oropharyngeal squamous cell carcinoma | 81 | 17:64 | 64 (49–87) | CD56 (NR) | NK cell presence; • present • absent |
NR | NR | No change, OS (NR) |
| Svensson et al.41 | 2017 | 2006 – 2010 | Head & Neck Cancer | Esophageal squamous cell carcinoma | 97 | NR | NR | NKp46 (NR) | Median NK cell number | Median (based on age) = 1.89 (<avg age) or 1.93 (> avg age) NK cells/ field Median (based on gender) = 1.99 (female) or 1.89 (male) cells/ field |
0.49 (0.28 – 0.86, p = 0.012) | Improved, OS (p = 0.008) |
| Taghavi et al.42 | 2016 | NR | Head & Neck Cancer | Oral squamous cell carcinoma | 57 | 30:27 | 62.89 (34–91) | CD57 (2H7), CD16 (NK-1) | Median NK cell number: • low <25 cells/ 25 fields • high >25 cells/ 25 fields |
Median = 25 cells/ 25 fields | 0.058 (0.013 – 0.26, p <0.001) | Improved, OS (p = 0.001) |
| Tsuchikawa et al.43 | 2011 | 1989 – 1999 | Head & Neck Cancer | Esophageal squamous cell carcinoma | 98 | 14:84 | 62.9 (53.9–71.9) | CD57 (Leu 7) | Quantified in the stroma: • abundant • scanty |
Median = 0.9 NK cells/ 200x field | NR | No change, OS (p = 0.31) |
| Wagner et al.44 | 2016 | 2000 – 2009 | Head & Neck Cancer | Oropharyngeal squamous cell carcinoma | 140 | 34:105 | 59 (38–84) | CD56 (1B6) | Quantified as: • CD56+ tumor & stroma • CD56+ stroma • CD56+ tumor • CD56+ absent |
NR | 0.32 (0.10 – 0.96, p = 0.042) | Improved, OS (p = 0.038) |
| Xu et al.45 | 2016 | 2006 – 2011 | Head & Neck Cancer | Esophageal squamous cell carcinoma | 138 | 36:102 | NR | CD57 (NR) | Quantified in the stroma: • Gr 3 (massive infiltration) • Gr 2 (abundant infiltration) • Gr 1 (moderate infiltration) • Gr 0 (scanty) |
NR | 0.60 (0.39 – 0.91, p = 0.016) | Improved, OS (p = 0.019) |
| Zancope et al.46 | 2010 | NR | Head & Neck Cancer | Oral and lip squamous carcinoma, Oral: 40 Lip: 30 |
70 |
64:36 | NR | CD57 (NK1) | Median NK cell number | Oral Epi: 14 cells/mm2 Oral Str: 145 cells/mm2 Lip Epi: 32 cells/mm2 |
NR | No change, OS Intra-epithelial (p = 0.70) Stromal (p = 0.69) |
| Honkanen et al.47 | 2017 | 2009 – 2014 | Breast Cancer | HER2+ | 48 | 48:0 | NR | CD56 (MRQ-42) | Quantified as: • low <17 cells/mm2 • high >17 cells/mm2 |
NR | NR | No change, OS (NR) |
| Muntasell et al.48 | 2018 | 2008 – 2016 | Breast Cancer | HER2+ | 113 DC: 42 VC: 71 |
113:0 | 57 (36–88) | CD56 (123C3) |
Quantified as: • low <1 cell • high >1 cell |
DC: 1.5 cells/ 50x VC: 2 cells/ 50x |
DC: 0.07 (0.01 – 0.60, p = 0.01) VC: 0.30 (0.08 – 1.30, p = 0.10) |
Improved, DFS (DC: p = 0.01, VC: p = 0.10) |
| Park et al.49 | 2012 | 1997 – 2002 | Breast Cancer | Invasive ductal carcinoma | 204 | 204:0 |
46= 113 patients >46= 85 patients |
CD57 (TB01) | Quantified as: • low (absent) • High (otherwise) |
Str: 1.10 cells/ | NR | No change, OS (p = 0.167) DFS (p = 0.358) |
| Rathore et al.50 | 2014 | NR | Breast Cancer | Invasive ductal carcinoma | 175 | 175:0 | 49.13 (25–86) | CD56 (NR) | Quantified in Str and Epi each as: • low <25 cells/ 25 fields • high >25 cells/ 25 fields |
NR | 1.92 (1.08 – 3.57, p = 0.05) | Poorer, OS (p = 0.05) |
| Tian et al.51 | 2016 | 2006 – 2008 | Breast Cancer | Invasive ductal carcinoma | 278 | 278:0 | Mean NR (28–75) | NKp46 (ab199128) | Quantified in Str based on density: • 0 (absent) • 3 (dense) |
NR | 0.54 (0.39 – 0.74, p = 0.001) | Improved, OS (p = 0.018) Improved DFS, (p < 0.001) |
| Triki et al.52 | 2019 | NR | Breast Cancer | NR | 158 | 158:0 | 118 patients>40 40 patients <40 |
CD56 (1BC) | Quantified as: • low (negative or weak infiltration) • high (moderate or strong infiltration) |
NR | 0.17 (0.039 – 0.73, p = 0.017) | Improved, OS ER+: p = 0.007 PR+: p = 0.018 HER+ p = 0.287 |
| Vgenopoulou et al.53 | 2003 | NR | Breast Cancer | Invasive ductal carcinoma | 64 | 64:0 | NR | CD57 (TB01) | Quantified based on staining intensity as: • Weak-moderate • Strong |
NR | NR | No change, DFS (NR) |
| Wang et al.54 | 2014 | 2006 – 2007 | Breast Cancer | ALDH1 high | 212 high, 379 low | 591:0 | 49 (23–87) | CD56 (NR) | Quantified as: • CD56 low <5 CD56+ cells • CD56 high >5 CD56+ cells |
NR | 1.10 (0.50 – 2.44, p = 0.81) | No change, OS (NR) |
| ALDH1 low | 0.11 (0.014 – 0.81, p = 0.031) | |||||||||||
| Alderdice et al.55 | 2017 | DC: 2004 – 2013 VC: 2001 - 2005 |
Colorectal Cancer | Locally advanced rectal cancer | 150 | NR | NR | CD56 (NCL-l-CD56–1B6) | Quantified as: • 〈 4 CD56+ cells • 〉 4 CD56+ cells |
NR | 0.28 (0.11 – 0.73, p = 0.005) | Improved, OS (NR) |
| Coca et al.56 | 1997 | 1977–1990 | Colorectal Cancer | 157 | 76:110 | 63.4 (29–84) | CD57 (IOT-10, Immunotech, SA) | NK cell infiltration classified as little (<50 NK cells), moderate (50–150 NK cells), and extensive (>150 NK cells) | NR | NR | Improved, OS and DFS (p < 0.01) | |
| Lim et al.57 | 2014 | 1998 – 2007 | Colorectal Cancer | Locally advanced rectal carcinoma | 52 | 18:34 | 63 (NR) | CD56 (NR) CD57 (NR) |
Median NK cell number | Median = 12 NK cells/1200x | NR | No change, OS (NR) |
| Liska et al.58 | 2012 | 2004 – 2007 | Colorectal Cancer | 150 | 53:97 | 66.33 (NR) | CD57 (NK1) | Quantified as: • 〈 4 NK cells • 〉 4 NK cells |
NR | 0.4 | Improved, OS (p = 0.035) |
|
| Menon et al.59 | 2004 | NR | Colorectal Cancer | 93 | 37:56 | 69 (26 – 85) | CD56 (123C3) CD57 (HNK1) |
Quantified based on staining intensity as: • None-poor • Moderate-marked |
CD56+ Epi: 5 cells/mm2 CD57+ Epi: 2 cells/mm2 |
0.43 (0.17 – 1.01, p = 0.03) | Improved, DFS (p = 0.05) |
|
| Sconocchia et al.60 | 2011 | NR | Colorectal Cancer | Mucinous (1301) Non-mucinous (174) |
1420 | 741:673 (3 NR) | 71 (30 – 96) | CD16 (NR) CD56 (NR) CD57 (NR) |
Quantified as: • <4 cells • >4 cells |
Mean = 0.14 ± 0.07 cells/HPF | 0.43 (0.3 – 0.7, p = 0.002) | No change, OS (NR) |
| Sconocchia et al.61 | 2014 | NR | Colorectal Cancer | 1410 | NR | NR | CD56 (NR) CD57 (NR) |
Quantified as: • 〈 4 CD56+ cells • 〉 4 CD56+ cells |
NR | NR | Improved, OS (p = 0.039) |
|
| Amoueian et al.62 | 2011 | 2004 – 2008 | Gastric Cancer | 50 | 12:38 | 68 (NR) | CD56 (123C3) | Quantified at both low (100x) and high (400x) power as: • low • high |
Mean = 8 cells/ 400x | NR | Improved, OS (NS) |
|
| Ishigami et al.63 | 2000 | 1988 – 1996 | Gastric Cancer | 169 | 48:121 | 63.8 (30 – 87) | CD57 (NR) | Quantified as: • low <25 cells/ 25 fields • high >25 cells/ 25 fields |
Mean = 0.9 cells/ 400x | NR | Improved, OS (p < 0.05) |
|
| Pernot et al.64 | 2020 | NR | Gastric Cancer | 40 | NR | 64 (34 – 83) | CD57 (NK1) | Quantified as: • low < 17% • high >17% |
Mean = 2.8 cells/mm2 | 0.40 (0.15 – 1.06, p = 0.04) | Improved, OS (p = 0.02) |
|
| Rusakiewicz et al.65 | 2013 | NR | Gastric Cancer | Gastrointestinal stromal tumors | 91 | 39:52 | 57 (NR) | NKp46 (195,314) | Median NK cell number | Epi: 3.7 cells/ 200x Str: 12.3 cells/ 200x |
0.2 (NR) | Improved, OS (p = 0.0001) |
| Svensson et al.41 | 2017 | 2006 – 2010 | Gastric Cancer | Gastric adenocarcinoma | 75 | NR | NR | NKp46 (NR) | Median NK cell number | Median (based on age) = 1.89 (<avg age) or 1.93 (> avg age) NK cells/ field Median (based on gender) = 1.99 (female) or 1.89 (male) cells/ field |
0.84 (0.41 – 1.70, p = 0.619) | No change, OS (p = 0.38) |
| Platonova et al.66 | 2011 | NR | Lung Cancer | Non-small cell lung carcinoma, squamous cell | 86 | 35:51 | 63.5 (39 –76) | NK46 (NR) | Quantified as: • low <9 cell • high >10 cell |
Mean Intratumoral NK cell = 15 cell/mm2 Mean stromal NK cells = 21 cells/mm2 |
NR | No change, OS (NR) |
| Takanami et al.67 | 2001 | 1989 – 1994 | Lung Cancer | Pulmonary adenocarcinoma | 150 | 67:83 | 61 (30 – 81) | CD57 (IOT-10) | Mean NK cell number | Mean = 32 cells/ field | 0.41 (p = 0.12) | Improved, OS (p = 0.0002) |
| Villegas et al.68 | 2002 | 1986 – 1997 | Lung Cancer | Squamous cell | 50 | 1:49 | 67.2 (50 – 81) | CD57 (NR) | Quantified as: • low <5 cells • high >5 cells |
Epi: 6.74 cells/ field | 0.43 (0.20 – 0.95, p = 0.036) | No change, OS (NR) |
| Yamada et al.69 | 2010 | 2007 – 2008 | Lung Cancer | Malignant Pleural Mesothelioma: Epithelioid: 26 Biphasic: 14 Sarcomatoid: 4 |
44 | 4:40 | 59 (35 – 85) | CD56 (1B6) | Median NK cell number | Median = 1.8 cells/ 400x Mean = 5.4 cells/ 400x |
0.66 (0.25 – 1.78, p = 0.41) | Improved, OS (p = 0.032) |
| Chew et al.70 | 2012 | 1991 – 2009 | Liver Cancer | Hepatocellular Carcinoma | 40 | NR | 59 (20 – 84) | CD56 (NR) | Median NK cell number | Median = 13 cells/ field | 0.12 (0.043 – 0.31, p < 0.001) | Improved, OS (p < 0.001) |
| Wu et al.71 | 2013 | 2000 – 2004 | Liver Cancer | Hepatocellular Carcinoma | 256 | NR | NR | CD57 (NK1) | Median intra-epithelial NK cell number | Median = 7 | 0.63 (0.40 – 0.99, p = 0.046) | Improved, OS and DFS (NR) |
| Zhao et al.72 | 2014 | 2003 – 2004 | Liver Cancer | Hepatocellular Carcinoma | 163 | 32:131 | NR | CD57 (NR) | Median number of CD57+ NK cells | NR | NR | Improved, OS (p = 0.002) |
| Zhu et al.73 | 2009 | 2002 – 2004 2006 – 2007 | Liver Cancer | Hepatocellular Carcinoma | 81 | 6:13, 9:53 | 55 (34 – 75) | CD56 (NR) | Quantified as: • low <1 cell • high >1 cell |
Epi (high) = 11.8 cells/ field Str (high) = 18 cells/ field Epi (low) = 2.3 cells/ field Str (low) = 8.5 cells/ field |
0.38 (0.17 – 0.85, p = 0.019) | Improved, OS (p = 0.005) |
| Henriksen et al.74 | 2019 | 2005 | Ovarian Cancer | High grade serous carcinoma | 283 | 283:0 | 63 (NR) | CD57 (NK1) | Quantified by ROC curve • low <9 cell • high >9 cell |
Median = 5 cells/mm2 | 0.67 (0.46 – 0.98, p = 0.041) | Improved, OS (p = 0.031) |
| Li et al.75 | 2009 | 1993 – 2003 | Ovarian Cancer | Serous, Clear, Transitional, Endometrioid | 82 | 82:0 | 55.3 (26 – 80) | CD57 (NR) | Quantified as: • CD56+ tumor & stroma • CD56+ stroma • CD56+ tumor • CD56+ absent |
Epi: > 1 cell/ 200x field in 61% of samples Str: > 2 cells/ 200x field in 40% of samples |
Epi 0.55 (0.188 – 1.607 p = 0.27) Str: 2.62 (1.007 – 6.818, p = 0.048) |
Epi: Improved, OS (p < 0.05) |
| Ino et al.76 | 2008 | 1992 – 2001 | Endometrial Cancer | 65 | 65:0 | 57.7 (NR) | CD57 (NR) | Quantified as: • low <5 cells • high >5 cells |
Median = 2 cells/ 200x | NR (p = 0.23) | No change, OS (p = 0.17) |
|
| Versluis et al.77 | 2017 | 1984 – 2004 | Endometrial Cancer | 355 | 355:0 | NR | NKp46 (195,314) | NK cell presence; • present • absent |
NR | HLA-E up-regulation 0.074 (0.0094 – 0.58, p = 0.014) HLA-E normal 0.64 (0.37 – 1.11, p = 0.115) |
Improved only if with HLA-3 upregulation (NR) | |
| Zinovkin et al.78 | 2016 | 2008 – 2009 | Endometrial Cancer | 82 | 82:0 | NR (45 – 80) | CD57 (NR) | Patients divided into; • Unfavourable outcome (recurrence or death within 5 years of diagnosis) • Favourable outcome |
Median CD57 in: Unfavourable group = 24.3% Favourable group = 45.6% |
NR | Improved, OS (p = 0.001) | |
| Sznurkowski et al.79 | 2014 | NR | Vulvar Cancer | Squamous cell carcinoma | 76 | 76:0 | 69.5 (36 – 85) | CD56 (123C3) | Median NK cell number | Median = 2 cells/ field | NR | Improved, OS (p = 0.0004) |
| Jasinski-Bergner et al.80 | 2015 | 1998 – 2011 | Kidney Cancer | Clear cell: 345 Papillary: 49 Chromophobe: 29 Other: 17 |
445 | 166:279 | 63.6 (23 – 92) | CD56 (MRQ-42) | Median NK cell number | Mean = 0.55 cells/ 400x field | NR | No change, OS (p = 0.91) |
| Jensen et al.81 | 2009 | 1992 – 2001 | Kidney Cancer | 121 | 61: 74 | 61 (19 – 82) | CD57 (NK1) | Quantified as: • low <28 cells/mm2 • high >28 cells/mm2 |
Median = 28 cells/mm2 | NR | No change, OS (p = 0.22) | |
| Sorbye et al.82 | 2012 | 1973 – 2006 1996 – 2006 |
Sarcoma | Soft tissue | 249 | 139:110 | NR (20 – 60) | CD57 (NR) | Quantified AS: • Gr 3 (20+ cells) • Gr 2 (6 – 19 cells) • Gr 1 (1 – 5 cells) • Gr 0 (no cells) |
NR | NR | No change, OS (p = 0.62) |
| Erdag et al.83 | 2012 | 1982 – 2007 | Melanoma | 147 | 63:84 | 58 (19 – 89) | CD56 | Median NK cell number | Epi = 5.1 cells/ mm2 Str = 2.5 cells/ mm2 |
NR | No change, OS (p = 0.43) | |
| Lundgren et al.84 | 2016 | 2001 – 2013 | Periampullary adenocarcinoma | Intestinal: 65 Pancreatobiliary: 110 |
175 | 82:90 | 67 (38 – 84) | CD56 (MRQ-42) | Quantified as: • low <2.75 cells/core • high >2.75 cells/core |
NR | Intestinal: 0.23 (0.07 – 0.78, p < 0.05) Pancreatobiliary: 0.59 (0.34 – 1.02, NR) |
Improved, OS (p = 0.002) |
| Nakakubo et al.85 | 2003 | 1989 – 1999 | Gallbladder cancer | Primary gallbladder adenocarcinoma | 45 | 28:17 | 66.7 (NR) | CD57 (Leu-7) | Quantified as: • 〈 10 NK cells/ HPF • 〉 10 NK cells/ HPF |
Mean = 1.2 cells/ 200x | 0.56 (0.20 – 1.58, p = 0.27) | No change, OS (p = 0.27) |
| Vaquero et al.86 | 1989 | NR | Glioblastoma | 25 | NR | 55.6 (19 – 69) | CD57 (IOT-10) | Divided into NK cell present or absent groups | Mean = 6 cells/ core | NR | No change, OS (NR) |