Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Institute of Gastroenterology, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of Immunobiology, School of Medicine, Yale University, CT, USA.
Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Institute of Gastroenterology, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Biomed Pharmacother. 2024 Apr;173:116427. doi: 10.1016/j.biopha.2024.116427. Epub 2024 Mar 13.
Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8T-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.
缺氧诱导因子 (HIFs) 调控 CD8T 细胞向肿瘤微环境迁移的机制尚不清楚。在这里，我们发现 HIF-1α 敲低或过表达分别导致体外 CXCL9、-10 和 -11 的表达增加或减少。基因集变异分析显示，HIF-1α 水平升高与结直肠癌 (CRC) 患者预后不良、病理分期严重以及肿瘤微环境中缺乏 CD8T 细胞相关。HIF-1α 与有利于抗肿瘤免疫治疗和细胞因子/趋化因子功能的途径呈负相关。在体内，抑制 HIF-1α 或其上游调节剂 BIRC2 可显著抑制肿瘤生长并促进 CD8T 细胞浸润。CXCR3 中和抗体逆转了这些效应，表明涉及 CXCL9、-10 和 -11/CXCR3 轴。HIF-1α 的存在削弱了博来霉素和阿霉素对 CXCL9、-10 和 -11 的上调作用。抑制 HIF-1α 与博来霉素联合使用可促进 CD8T 细胞浸润和体内肿瘤抑制。此外，阿霉素通过抑制 HIF-1α 可上调 CXCL9、-10 和 -11。我们的研究结果强调了抑制 HIF-1α 以改善 CRC 微环境和增加化疗敏感性的潜力。
