Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma
© 2018 by the American Association for the Study of Liver Diseases..
Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Coinhibitory CD96 and T-cell immunoglobulin and ITIM domain (TIGIT), together with costimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine-tunes immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT, and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin-embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and mean fluorescence intensity (MFI) of CD96+ NK cells are significantly increased in the intratumoral tissues of HCC and break the balance between three receptors. Human CD96+ NK cells are functionally exhausted with impaired interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) production, high gene expression of interleukin (IL)-10 and transforming growth factor-beta 1 (TGF-β1), and low gene expression of T-bet, IL-15, perforin, and granzyme B. In addition, blocking CD96-CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with a high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition and shorter disease-free survival (DFS) and overall survival times. Patients with a higher cumulative percentage of CD96+ NK cells within tumor also exhibit shorter DFS. High plasma level of TGF-β1 in HCC patients up-regulates CD96 expression and dynamically shifts the balance between CD96, TIGIT, and CD226 in NK cells. Blocking TGF-β1 specifically restores normal CD96 expression and reverses the dysfunction of NK cells. Conclusion: These findings indicate that human intratumoral CD96+ NK cells are functionally exhausted and patients with higher intratumoral CD96 expression exhibit poorer clinical outcomes. Blocking CD96-CD155 interaction or TGF-β1 restores NK cell immunity against tumors by reversing NK cell exhaustion, suggesting a possible therapeutic role of CD96 in fighting liver cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:70 |
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| Enthalten in: |
Hepatology (Baltimore, Md.) - 70(2019), 1 vom: 28. Juli, Seite 168-183 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Haoyu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.06.2020 Date Revised 22.06.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/hep.30347 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM290441196 |
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| 100 | 1 | |a Sun, Haoyu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 22.06.2020 | ||
| 500 | |a Date Revised 22.06.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2018 by the American Association for the Study of Liver Diseases. | ||
| 520 | |a Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Coinhibitory CD96 and T-cell immunoglobulin and ITIM domain (TIGIT), together with costimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine-tunes immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT, and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin-embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and mean fluorescence intensity (MFI) of CD96+ NK cells are significantly increased in the intratumoral tissues of HCC and break the balance between three receptors. Human CD96+ NK cells are functionally exhausted with impaired interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) production, high gene expression of interleukin (IL)-10 and transforming growth factor-beta 1 (TGF-β1), and low gene expression of T-bet, IL-15, perforin, and granzyme B. In addition, blocking CD96-CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with a high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition and shorter disease-free survival (DFS) and overall survival times. Patients with a higher cumulative percentage of CD96+ NK cells within tumor also exhibit shorter DFS. High plasma level of TGF-β1 in HCC patients up-regulates CD96 expression and dynamically shifts the balance between CD96, TIGIT, and CD226 in NK cells. Blocking TGF-β1 specifically restores normal CD96 expression and reverses the dysfunction of NK cells. Conclusion: These findings indicate that human intratumoral CD96+ NK cells are functionally exhausted and patients with higher intratumoral CD96 expression exhibit poorer clinical outcomes. Blocking CD96-CD155 interaction or TGF-β1 restores NK cell immunity against tumors by reversing NK cell exhaustion, suggesting a possible therapeutic role of CD96 in fighting liver cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antigens, CD |2 NLM | |
| 650 | 7 | |a Antigens, Differentiation, T-Lymphocyte |2 NLM | |
| 650 | 7 | |a CD226 antigen |2 NLM | |
| 650 | 7 | |a CD96 antigen |2 NLM | |
| 650 | 7 | |a Receptors, Immunologic |2 NLM | |
| 650 | 7 | |a Receptors, Virus |2 NLM | |
| 650 | 7 | |a TGFB1 protein, human |2 NLM | |
| 650 | 7 | |a TIGIT protein, human |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 650 | 7 | |a poliovirus receptor |2 NLM | |
| 700 | 1 | |a Huang, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Renyong |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Meijuan |e verfasserin |4 aut | |
| 700 | 1 | |a Qu, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Haiming |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Weihua |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Zhigang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Cheng |e verfasserin |4 aut | |
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