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

• DOI: 10.1016/j.biopha.2024.116427
• Publication Date: 2024-03-13T19:28:56Z
• Authors: Yixi Su; Jiaqi Liu; Yu Tian; Haiyan Dong; Mengchen Shi; Jingdan Zhang; Weiqian Li; Qiang Huang; Nanlin Xiang; Chen Wang; Jun Liu; Lingyuan He; Limei Hu; Ann M. Haberman; Huanliang Liu; Xiangling Yang
• Keywords: 0301 basic medicine; CD8-Positive T-Lymphocytes; Hypoxia-Inducible Factor 1, alpha Subunit; Chemokine CXCL9; Bleomycin; 03 medical and health sciences; Doxorubicin; Drug Resistance, Neoplasm; Cell Line, Tumor; Tumor Microenvironment; Humans; Cytokines; Colorectal Neoplasms

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.