HIF-1α Mediates Immunosuppression and Chemoresistance in Colorectal Cancer by Inhibiting CXCL9, −10 and −11 - 22/03/24
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | HIF-1α protein inhibits the expression of CXCL9, −10 and −11 in CRC. |
• | BIRC2 promotes the expression of HIF-1α protein in CRC cell lines. |
• | Knockdown of HIF-1α improves the anti-tumor impact of Bleomycin or Doxorubicin. |
Abbreviations : TME, CRC, HIF, HRE, BIRC2, VEGFA, PD-L1, Th1, CXCL9, CXCL10, CXCL11, MHC-I, ICD, IC50, NK cell, MRP1, WB, QPCR, CCK-8, IHC, ELISA, HPA, TCGA, GSVA, GSEA, SsGSEA, OS, NES, BLM, DOX, IOD
Keywords : HIF-1α, BIRC2, CXCL9, CXCL10, CXCL11, CD8+ T Cell, Chemo-immunotherapy, Colorectal Cancer
Plan
Vol 173
Article 116427- avril 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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