M2‐like macrophage polarization in high lactic acid‐producing head and neck cancer

Abstract

Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect and results in increased lactic acid secretion into the tumor microenvironment. We have previously shown that lactic acid has important roles as a pro‐inflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of LDHA and GLUT1, which are related to the Warburg effect, in human head and neck squamous cell carcinoma (HNSCC). Tumors expressing lower levels of LDHA and GLUT1 had a higher concentration of lactic acid than those with higher LDHA and GLUT1 expression. Lactic acid also suppressed the expression of LDHA and GLUT1 in vitro. We previously reported that lactic acid enhances expression of an M2 macrophage marker, ARG1, in murine macrophages. Therefore, we investigated the relationship between the lactic acid concentration and polarization of M2 macrophages in HNSCC by measuring the expression of M2 macrophage markers, CSF1R and CD163, normalized using a pan‐macrophage marker, CD68. Tumors with lower levels of CD68 showed a higher concentration of lactic acid, whereas those with higher levels of CSF1R showed a significantly higher concentration of lactic acid. A similar tendency was observed for CD163. These results suggest that tumor‐secreted lactic acid is linked to the reduction of macrophages in tumors and promotes induction of M2‐like macrophage polarization in human HNSCC.

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

“…Lactate prevents cytokine release and monocyte migration, while promotes the formation of tumor-associated macrophage 2 (TAM2) phenotype. It leads to upregulate the expression of arginase 1, promote immune escape and tumor progression (25,(76)(77)(78). Lactate reduces the production of IFN-γ from T cells and NK cells, and decreases the level of nuclear factor of activated T cells (NFAT), which also contributes to immune escape and tumor progression (79,80).…”

Chitinase-3-Like-1 Promotes M2 Macrophage Differentiation and Induces Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration

“…To further validate, we tested the ability of CHI3L1 to promote M2 differentiation in vitro. As Arg-1 and Ym-1 are consistently expressed by M2 macrophage, 30,31 we stimulated macrophage with recombinant CHI3L1 and M2 markers (Ym-1 and Arg-1) were subsequently identified by immune staining and Western blot (Figs. 3B-D).…”

Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma

“…Moreover, studies show the correlation between the density of CAFs and TAMs with poor outcome in HNSCC (59,60). Furthermore, one study reported that protumorigenic macrophage polarization is promoted in HNSCC tumors with high lactic acid concentrations (61). Interestingly, CS fibroblasts in our model secrete much higher lactate than CTRL fibroblasts.…”