Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
J Clin Invest. 2022 Apr 1;132(7). doi: 10.1172/JCI153110.
Macrophages constitute a major immune component in tumor tissues, but how these cells adapt to and survive in the nutrient-depleted and lactic acid-induced acidic tumor microenvironments is not yet fully understood. Here, we found that levels of carbonic anhydrase XII (CA12) expression were significantly and selectively upregulated on macrophages in human hepatocellular carcinoma (HCC). Transient glycolytic activation of peritumoral monocytes induced sustained expression of CA12 on tumor-infiltrating macrophages via autocrine cytokines and HIF1α pathways. On the one hand, CA12 mediated the survival of macrophages in relatively acidic tumor microenvironments, while on the other hand, it induced macrophage production of large amounts of C-C motif chemokine ligand 8 (CCL8), which enhanced cancer cell epithelial-mesenchymal transition (EMT) and facilitated tumor metastasis. Consistently, the accumulation of CA12+ macrophages in tumor tissues was associated with increased tumor metastatic potential and reduced survival of patients with HCC. Selective targeting of tumor-infiltrating macrophages with a CA12 inhibitor reduced tumor growth in mice and was sufficient to synergistically enhance the therapeutic efficacy of immune-checkpoint blockade. We suggest that CA12 activity is a previously unappreciated mechanism regulating the accumulation and functions of macrophages in tumor microenvironments and therefore represents a selective vulnerability that could be exploited in future designs for antitumor immunotherapeutic strategies.
肿瘤组织中的巨噬细胞构成了主要的免疫成分，但这些细胞如何适应和在营养匮乏且乳酸诱导的酸性肿瘤微环境中存活尚不完全清楚。在这里，我们发现人肝癌 (HCC) 中的巨噬细胞上碳酸酐酶 XII (CA12) 的表达水平显著且选择性地上调。肿瘤周围单核细胞的短暂糖酵解激活通过自分泌细胞因子和 HIF1α 途径诱导肿瘤浸润巨噬细胞持续表达 CA12。一方面，CA12 介导了巨噬细胞在相对酸性肿瘤微环境中的存活，另一方面，它诱导巨噬细胞大量产生 C-C 基序趋化因子配体 8 (CCL8)，从而增强癌细胞上皮-间充质转化 (EMT) 并促进肿瘤转移。一致地，肿瘤组织中 CA12+巨噬细胞的积累与增加的肿瘤转移潜力和 HCC 患者的生存减少有关。用 CA12 抑制剂选择性靶向肿瘤浸润巨噬细胞可减少小鼠的肿瘤生长，并足以协同增强免疫检查点阻断的治疗效果。我们认为，CA12 活性是调节肿瘤微环境中巨噬细胞积累和功能的以前未被认识的机制，因此代表了一种选择性脆弱性，可以在未来的抗肿瘤免疫治疗策略设计中加以利用。
