Interferon-α induces differentiation of cancer stem cells and immunosuppression in hepatocellular carcinoma by upregulating CXCL8 secretion
Copyright © 2024 Elsevier Ltd. All rights reserved..
Interferon-alpha (IFN-α) is widely used in the clinical treatment of patients with chronic hepatitis B and hepatocellular carcinoma (HCC). However, high levels of CXCL8 are associated with resistance to IFN-α therapy and poorer prognosis in advanced cancers. In this study, we investigated whether IFN-α could directly induce the production of CXCL8 in HCC cells and whether CXCL8 could antagonize the antitumor activity of IFN-α. We found that IFN-α not only upregulated the expression of the inducible genes CXCL9, CXCL10, CXCL11 and PD-L1, but also significantly stimulated CXCL8 secretion in HCC cells. Mechanically, IFN-α induces CXCL8 expression by activating the AKT and JNK pathways. In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic. Besides, our study reveals that the cytokine CXCL8 secreted by IFN-α-induced HCC cells inhibits T-cell function. Conversely, inhibition of CXCL8 promotes TNF-α and IFN-γ secretion by T cells. Finally, liver cancer patients who received anti-PD-1/PD-L1 immunotherapy with high CXCL8 expression had a lower immunotherapy efficacy. Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:177 |
|---|---|
| Enthalten in: |
Cytokine - 177(2024) vom: 09. Apr., Seite 156555 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ma, Yu-Ting [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
82115-62-6 |
|---|
| Anmerkungen: |
Date Completed 13.03.2024 Date Revised 08.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.cyto.2024.156555 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36877225X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36877225X | ||
| 003 | DE-627 | ||
| 005 | 20240409232502.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.cyto.2024.156555 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1370.xml |
| 035 | |a (DE-627)NLM36877225X | ||
| 035 | |a (NLM)38387232 | ||
| 035 | |a (PII)S1043-4666(24)00058-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ma, Yu-Ting |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Interferon-α induces differentiation of cancer stem cells and immunosuppression in hepatocellular carcinoma by upregulating CXCL8 secretion |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 13.03.2024 | ||
| 500 | |a Date Revised 08.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Interferon-alpha (IFN-α) is widely used in the clinical treatment of patients with chronic hepatitis B and hepatocellular carcinoma (HCC). However, high levels of CXCL8 are associated with resistance to IFN-α therapy and poorer prognosis in advanced cancers. In this study, we investigated whether IFN-α could directly induce the production of CXCL8 in HCC cells and whether CXCL8 could antagonize the antitumor activity of IFN-α. We found that IFN-α not only upregulated the expression of the inducible genes CXCL9, CXCL10, CXCL11 and PD-L1, but also significantly stimulated CXCL8 secretion in HCC cells. Mechanically, IFN-α induces CXCL8 expression by activating the AKT and JNK pathways. In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic. Besides, our study reveals that the cytokine CXCL8 secreted by IFN-α-induced HCC cells inhibits T-cell function. Conversely, inhibition of CXCL8 promotes TNF-α and IFN-γ secretion by T cells. Finally, liver cancer patients who received anti-PD-1/PD-L1 immunotherapy with high CXCL8 expression had a lower immunotherapy efficacy. Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CXCL8 | |
| 650 | 4 | |a Hepatocellular carcinoma | |
| 650 | 4 | |a IFN-α | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a Interferon-alpha |2 NLM | |
| 650 | 7 | |a Interferon-gamma |2 NLM | |
| 650 | 7 | |a 82115-62-6 |2 NLM | |
| 650 | 7 | |a Interleukin-8 |2 NLM | |
| 700 | 1 | |a Zheng, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Cheng-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Xin-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xin-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Niu, Guo-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Man, Zhong-Song |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yong-Qiang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cytokine |d 1994 |g 177(2024) vom: 09. Apr., Seite 156555 |w (DE-627)NLM012645575 |x 1096-0023 |7 nnns |
| 773 | 1 | 8 | |g volume:177 |g year:2024 |g day:09 |g month:04 |g pages:156555 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.cyto.2024.156555 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 177 |j 2024 |b 09 |c 04 |h 156555 | ||