Regulation of tumor-associated macrophage (TAM) differentiation by NDRG2 expression in breast cancer cells
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Macrophages are a major cellular component of innate immunityand are mainly known to have phagocytic activity. In the tumormicroenvironment (TME), they can be differentiated into tumorassociatedmacrophages (TAMs). As the most abundant immunecells in the TME, TAMs promote tumor progression by enhancingangiogenesis, suppressing T cells and increasing immunosuppressivecytokine production. N-myc downstream-regulated gene 2(NDRG2) is a tumor suppressor gene, whose expression is downregulatedin various cancers. However, the effect of NDRG2on the differentiation of macrophages into TAMs in breast cancerremains elusive. In this study, we investigated the effect ofNDRG2 expression in breast cancer cells on the differentiationof macrophages into TAMs. Compared to tumor cell-conditionedmedium (TCCM) from 4T1-mock cells, TCCM from NDRG2-overexpressing4T1 mouse breast cancer cells did not significantlychange the morphology of RAW 264.7 cells. However, TCCMfrom 4T1-NDRG2 cells reduced the mRNA levels of TAM-relatedgenes, including MR1, IL-10, ARG1 and iNOS, in RAW 264.7cells. In addition, TCCM from 4T1-NDRG2 cells reduced theexpression of TAM-related surface markers, such as CD206, inperitoneal macrophages (PEM). The mRNA expression of TAMrelatedgenes, including IL-10, YM1, FIZZ1, MR1, ARG1 andiNOS, was also downregulated by TCCM from 4T1-NDRG2cells. Remarkably, TCCM from 4T1-NDRG2 cells reduced theexpression of PD-L1 and Fra-1 as well as the production ofGM-CSF, IL-10 and ROS, leading to the attenuation of T cellinhibitoryactivity of PEM. These data showed that comparedwith TCCM from 4T1-mock cells, TCCM from 4T1-NDRG2 cellssuppressed the TAM differentiation and activation. Collectively,these results suggest that NDRG2 expression in breast cancermay reduce the differentiation of macrophages into TAMs inthe TME.
Abstract
Macrophages are a major cellular component of innate immunityand are mainly known to have phagocytic activity. In the tumormicroenvironment (TME), they can be differentiated into tumorassociatedmacrophages (TAMs). As the most abundant immunecells in the TME, TAMs promote tumor progression by enhancingangiogenesis, suppressing T cells and increasing immunosuppressivecytokine production. N-myc downstream-regulated gene 2(NDRG2) is a tumor suppressor gene, whose expression is downregulatedin various cancers. However, the effect of NDRG2on the differentiation of macrophages into TAMs in breast cancerremains elusive. In this study, we investigated the effect ofNDRG2 expression in breast cancer cells on the differentiationof macrophages into TAMs. Compared to tumor cell-conditionedmedium (TCCM) from 4T1-mock cells, TCCM from NDRG2-overexpressing4T1 mouse breast cancer cells did not significantlychange the morphology of RAW 264.7 cells. However, TCCMfrom 4T1-NDRG2 cells reduced the mRNA levels of TAM-relatedgenes, including MR1, IL-10, ARG1 and iNOS, in RAW 264.7cells. In addition, TCCM from 4T1-NDRG2 cells reduced theexpression of TAM-related surface markers, such as CD206, inperitoneal macrophages (PEM). The mRNA expression of TAMrelatedgenes, including IL-10, YM1, FIZZ1, MR1, ARG1 andiNOS, was also downregulated by TCCM from 4T1-NDRG2cells. Remarkably, TCCM from 4T1-NDRG2 cells reduced theexpression of PD-L1 and Fra-1 as well as the production ofGM-CSF, IL-10 and ROS, leading to the attenuation of T cellinhibitoryactivity of PEM. These data showed that comparedwith TCCM from 4T1-mock cells, TCCM from 4T1-NDRG2 cellssuppressed the TAM differentiation and activation. Collectively,these results suggest that NDRG2 expression in breast cancermay reduce the differentiation of macrophages into TAMs inthe TME.
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