An acid trip activates protumoral macrophages to promote hepatocellular carcinoma malignancy
Nicola Graham, Jeffrey W. Pollard
Nicola Graham, Jeffrey W. Pollard
Published April 1, 2022
Citation Information: J Clin Invest. 2022;132(7):e158562. https://doi.org/10.1172/JCI158562.
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Commentary

An acid trip activates protumoral macrophages to promote hepatocellular carcinoma malignancy

Abstract

Tumor-associated macrophages (TAMs) promote metastasis and tumor cell extravasation, survival, and growth. In hepatocellular carcinoma (HCC), the presence of TAM subpopulations correlates with poor outcome. In this issue of the JCI, Ning et al. report on their use of cell culture, mouse models, and human data sets to investigate the interactions between aerobic glycolysis and carbonic anhydrase XII (CA12) expression in HCC. Aerobic glycolysis promoted CA12 upregulation in TAMs, which induced a protumoral phenotype to promote tumor growth and metastasis. Tumor cell factors derived from HCC samples induced CA12 upregulation in tumor-infiltrating TAMs via the HIF1α pathway. In preclinical models of HCC, CA12 inhibition reduced tumor growth and lung metastasis and reduced TAM infiltrate. Notably, dual treatment with anti-PD1 and CA12 inhibitors synergistically attenuated tumor growth and metastasis and enhanced survival compared with either treatment alone. These findings suggest that targeting CA12 in combination with immune-checkpoint blockade may provide treatment options for HCC.

Authors

Nicola Graham, Jeffrey W. Pollard

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Figure 1

CA12 activity regulates the accumulation and functions of macrophages in TMEs.

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CA12 activity regulates the accumulation and functions of macrophages in...
(A) CA12 inhibition reduces tumor growth and lung metastasis in preclinical mouse models of HCC. Targeting CA12 using CA12 inhibitors (CA12i) attenuated tumor growth and metastasis and displayed synergistic effects with anti-PD1 therapy. (B). Factors secreted from the tumor cells during hypoxia and acid accumulation induce aerobic glycolysis in tumor-associated monocytes/macrophages via the activation of the HIF1α-signaling pathway, indicated by increased glucose transporter GLUT1. The factors also induce CA12 and several cytokines, including TNF-α, IL-10, and IL-1β, which act in an autocrine manner to further induce CA12 expression. Notably, CA12 exhibits a protective function, promoting macrophage survival by preventing apoptosis in the acidic environment. CA12 also promotes CCL8 secretion in a p38-dependent manner, which acts on the tumor cells to induce EMT and promote tumor growth and metastasis. Targeting of this molecular pathway using relevant inhibitors could disrupt this mechanism in HCC.