Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages

Abstract

The enzyme 5-lipoxygenase (5-LO) is key in the synthesis of leukotrienes, which are potent proinflammatory lipid mediators involved in chronic inflammatory diseases including cancer. 5-LO is expressed in immune cells but also found in cancer cells. Although the role of 5-LO in tumor cells is beginning to emerge, with the notion that tumor-promoting functions are attributed to its products, the function of 5-LO in the tumor microenvironment remains unclear. To understand the role of 5-LO and its products in the tumor microenvironment, we analyzed its expression and function in tumor-associated macrophages (TAMs). TAMs were generated by coculturing primary human macrophages (MΦ) with human MCF-7 breast carcinoma cells, which caused cell death of cancer cells followed by phagocytosis of cell debris by MΦ. Expression and activity of 5-LO in TAMs were reduced upon coculture with cancer cells. Downregulation of 5-LO in TAMs required tumor cell death and the direct contact between MΦ and dying cancer cells via Mer tyrosine kinase. Subsequently, upregulation of proto-oncogene c-Myb in TAMs induced a stable transcriptional repression of 5-LO. Reduced 5-LO expression in TAMs was mechanistically coupled to an attenuated T cell recruitment. In primary TAMs from human and murine breast tumors, 5-LO expression was absent or low when compared with monocyte-derived MΦ. Our data reveal that 5-LO, which is required for leukotriene production and subsequent T cell recruitment, is downregulated in TAMs through Mer tyrosine kinase-dependent recognition of apoptotic cancer cells. Mechanistically, we noticed transcriptional repression of 5-LO by proto-oncogene c-Myb and conclude that loss of stromal 5-LO expression favors tumor progression.

Eicosanoids in Cancer: New Roles in Immunoregulation

“…While other factors, specifically ligands which bind to CXCR3 on T cells, such as CXCL9 and CXCL10 are critical for T cell recruitment to tumors, deletion of BLT1 and CXCR3 result in equal impairments in T cell recruitment, and the double knockout mice do not show any additivity, suggesting that both of these pathways are required (Chheda et al, 2016). Consistent with these data, apoptotic cancer cells have been shown to reduce expression of 5-lipoxygenase in tumor associated macrophages, and this is associated with decreased T cell recruitment and tumor progression (Ringleb et al, 2018). Interestingly, the response of melanoma tumors to immune checkpoint inhibitors such as anti-PD-1 is abrogated if these tumors are growing in BLT1-deficient mice (Chheda et al, 2016).…”

“…This is likely due to pro-tumorigenic effects of other 5-LO products, such as LTC4. Tumor-associated macrophages show a decreased expression for 5-lipoxygenase which appears to be mediated through direct cell-cell contact and MerTK signaling (Ringleb et al, 2018). These authors suggest that 5-LO may be marker for tumor associated macrophages (TAMs).…”

Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer

“…At different time points, we collected macrophages and tumor cells for FACS, RNA (TRIzol), protein expression [radioimmunoprecipitation assay (RIPA) buffer], and cellular assays. Further, we transfected or treated attached macrophages (days 3 and 5) with the required agents, as described in the following sections (38,39).…”

Sea Hare Hydrolysate-Induced Reduction of Human Non-Small Cell Lung Cancer Cell Growth through Regulation of Macrophage Polarization and Non-Apoptotic Regulated Cell Death Pathways

“…TAMs were produced to identify SHH's effect on tissue-resident macrophages present in the tumor microenvironment. M0 cells were cocultured with A549 cells at a 1:1 ratio for 4 days to establish a TAM-like phenotype, with and without SHH treatment, as previously described [24]. The cells were washed at the end of the incubation to remove the remaining cancer cells from the culture dish.…”