Editors' ChoiceCancer

When ER stress is bad for cancer

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Sci. Signal.  01 May 2018:
Vol. 11, Issue 528, eaau0066
DOI: 10.1126/scisignal.aau0066

A low-protein diet enhances tumor immunosurveillance in multiple cancer types.

Dietary restriction, such as caloric restriction, enhances tumor immunosurveillance but can be difficult to implement in patients. Rubio-Patiño et al. (see also the commentary by Green) found that the beneficial effects of dietary restriction on tumor immunosurveillance were mimicked by a diet that limited protein intake. Lymphoma, colorectal carcinoma, or melanoma growth was decreased and survival was increased by feeding mice a low-protein diet but not an isocaloric low-carbohydrate diet. These effects were mediated by cytotoxic CD8+ T cells. T cells from mice on a low-protein diet were more effective at killing syngeneic tumor cells than were those from mice on a normal or low-carbohydrate diet. Moreover, mice on a low-protein diet had more intratumoral natural killer cells and CD3+CD8+ T lymphocytes. The low-protein diet induced a type of endoplasmic reticulum (ER) stress called the unfolded protein response (UPR) in tumor cells, resulting in the activation of the UPR effector IRE1α and the RNA sensor RIG-I. Treating mice with inhibitors of ER stress or IRE1α or genetically ablating IRE1α or RIG-I in colorectal carcinoma cells with CRISPR/Cas9 blocked the beneficial effects of a low-protein diet on tumor burden. In the Cancer Genome Atlas (TCGA) datasets, gene signatures associated with IRE1α activation correlated with increased expression of T cell markers in three different cancer types. The authors conclude that the proportions of macronutrients are more important than the caloric value in determining the effect of diet on tumor immunosurveillance.

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