HIF-1α Mediates Immunosuppression and Chemoresistance in Colorectal Cancer by Inhibiting CXCL9, -10 and -11
Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression resulted in increased or decreased CXCL9, -10, and -11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, -10, and -11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, -10, and -11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, -10 and -11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:173 |
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| Enthalten in: |
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie - 173(2024) vom: 30. März, Seite 116427 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Su, Yixi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.biopha.2024.116427 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369742451 |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression resulted in increased or decreased CXCL9, -10, and -11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, -10, and -11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, -10, and -11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, -10 and -11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BIRC2 | |
| 650 | 4 | |a CD8(+) T Cell | |
| 650 | 4 | |a CXCL10 | |
| 650 | 4 | |a CXCL11 | |
| 650 | 4 | |a CXCL9 | |
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| 650 | 7 | |a Hypoxia-Inducible Factor 1, alpha Subunit |2 NLM | |
| 700 | 1 | |a Liu, Jiaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Haiyan |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Mengchen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jingdan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Weiqian |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Xiang, Nanlin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a He, Lingyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Limei |e verfasserin |4 aut | |
| 700 | 1 | |a Haberman, Ann M |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Huanliang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xiangling |e verfasserin |4 aut | |
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