Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

Abstract

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

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“…Although the underlying mechanisms have not been completely characterised, metformin reduces tumour cell growth, inhibits the expression of microRNAs associated with tumorigenesis, and limits energy availability by affecting mitochondrial metabolism [4] . Moreover, cell starvation caused by metformin triggers the release of cytokines such as interleukins IL-6 and IL-8, and promotes recruitment of immune cells in the tumour microenvironment [5] .…”

“… [ 9 , 12 ] Counteracts tumour angiogenesis and endothelial dysfunction in ARDS Ivermectin Antiparasitic agent Inhibits nuclear import mechanisms of oncoproteins and viral proteins. [ 19 , 21 ] Induces immunogenic cell death Metformin Hypoglycaemic drug Among various effects, triggers cytokine release and recruits immune cells [ 1 , 5 ] Nitazoxanide Antiparasitic agent Not clearly defined. Induces cell cytotoxicity under hypoxic conditions [ 1 , 3 ] ARDS, acute respiratory disease syndrome.…”

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“…. ) in an ATF4-and NF-κB-dependent manner in response to starvation, inducing the chemotaxis of macrophages, B cells and neutrophils [269]. Whether DR signalling is also involved in this case would be interesting to determine.…”

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“…Studies correlating cancer metabolism and immune dysfunction are flourishing. Interestingly, cytokine secretion by tumor cells is regulated by external stimuli and stressors such as glucose deprivation, as shown in a model of lung cancer [ 137 ] and this might represent an additional mechanism of immune regulation in solid tumors.…”