Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance

Abstract

Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 + T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors. Dietary restriction (DR) slows down tumor growth by increasing tumor immunosurveillance. Rubio-Patiño et al. show that a moderate reduction in dietary protein intake, rather than carbohydrate reduction, without overall calorie changes, activates the IRE1α/RIG1 pathway in tumor cells resulting in an anticancer immune response in mice. © 2018 Elsevier Inc.