Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, L- 1210, Luxembourg.
Department of Hemato-Oncology, Centre Hospitalier du Luxembourg, Luxembourg, L- 1210, Luxembourg.
Sci Rep. 2024 Nov 4;14(1):26589. doi: 10.1038/s41598-024-77628-8.
Lack of significant and durable clinical benefit from anti-cancer immunotherapies is partly due to the failure of cytotoxic immune cells to infiltrate the tumor microenvironment. Immune infiltration is predominantly dependent on the chemokine network, which is regulated in part by chemokine and atypical chemokine receptors. We investigated the impact of hypoxia in the regulation of Atypical Chemokine Receptor 2 (ACKR2), which subsequently regulates major pro-inflammatory chemokines reported to drive cytotoxic immune cells into the tumor microenvironment. Our in silico analysis showed that both murine and human ACKR2 promoters contain hypoxia response element (HRE) motifs. Murine and human colorectal, melanoma, and breast cancer cells overexpressed ACKR2 under hypoxic conditions in a HIF-1α dependent manner; as such overexpression was abrogated in melanoma cells expressing non-functional deleted HIF-1α. We also showed that decreased expression of ACKR2 in HIF-1α-deleted cells under hypoxia was associated with increased CCL5 levels. Chromatin immunoprecipitation data confirmed that ACKR2 is directly regulated by HIF-1α at its promoter in B16-F10 melanoma cells. This study provides new key elements on how hypoxia can impair immune infiltration in the tumor microenvironment.
抗癌免疫疗法缺乏显著和持久的临床获益，部分原因是细胞毒性免疫细胞未能浸润肿瘤微环境。免疫浸润主要依赖趋化因子网络，该网络部分受趋化因子和非典型趋化因子受体调节。我们研究了缺氧对非典型趋化因子受体 2 (ACKR2)调节的影响，ACKR2 随后调节主要促炎趋化因子，这些趋化因子被报道可驱动细胞毒性免疫细胞进入肿瘤微环境。我们的计算机分析表明，鼠和人 ACKR2 启动子都含有缺氧反应元件 (HRE) 基序。在缺氧条件下，鼠和人结直肠、黑色素瘤和乳腺癌细胞以 HIF-1α 依赖的方式过表达 ACKR2；因此，在表达无功能缺失 HIF-1α 的黑色素瘤细胞中，过表达被阻断。我们还表明，在缺氧下 HIF-1α 缺失细胞中 ACKR2 的表达减少与 CCL5 水平的增加有关。染色质免疫沉淀数据证实，在 B16-F10 黑色素瘤细胞中，ACKR2 可在其启动子处被 HIF-1α 直接调节。这项研究提供了新的关键因素，说明了缺氧如何损害肿瘤微环境中的免疫浸润。
