Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma

Abstract

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 HIF1 α 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.

F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production

“… 9 , 18 , 19 Besides, the tumor microenvironment has also been identified to play a determinative role in fostering tumor growth and metastasis. 45 , 46 Here, we confirmed that F. nucleatum colonized in OSCC tissues could induce cancer cells to produce much more lactate via the GalNAc-Autophagy-TBC1D5-GLUT1 signaling axis. TBC1D5 degradation leads to GLUT1 localization on the cell surface and glucose uptake, which is metabolized to lactate, subsequently promoting M2-like TAMs formation.…”

Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer

“… 12 13 The functional heterogeneities of TAMs are associated with phenotypic subsets, that is, tumor-inhibiting M1-like and tumor-promoting M2-like macrophages. 14 15 Under normal circumstances, the biological function of M2 macrophages is to inhibit inflammation and promote tissue repair. 16 M2 TAMs enhance cancer cell invasion, regulate T cell function, and promote tumor progression.…”

Integrative Proteomic and Phosphoproteomic Analyses of Hypoxia-Treated Pulmonary Artery Smooth Muscle Cells

“…It has been reported that the expression of CA12 has increased in human colon adenocarcinoma cells in a HIF1α-dependent manner and is necessary for tumor cell proliferation both in vivo and in vitro [ 27 ]. The latest study found that CA12 mediated the prometastatic functions of human hepatocellular carcinoma-associated macrophages [ 28 ]. While unspecifically inhibiting carbonic anhydrase ameliorates inflammation and experimental pulmonary hypertension and carbonic anhydrase IX plays important roles in regulating pulmonary microvascular endothelial cell pH and angiogenesis during acidosis, the functions of CA12 in PAH have not been studied yet [ 29 , 30 ].…”