HIF-1α Mediates Immunosuppression and Chemoresistance in Colorectal Cancer by Inhibiting CXCL9, ?10 and ?11

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.

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