Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival

Simple Summary Despite the advances in the treatment of pre-B-ALL leukemia in children, adult pre-B-ALL continues to represent a major challenge. This work focuses on the use of differential responses to fasting conditions between normal and cancer cells to achieve cancer-free survival. We show that a fasting-mimicking diet in combination with vincristine causes a synergistic increase in the toxicity to pre-B-ALL cells resulting in high cancer cell death. While fasting is not sufficient to promote cancer-free survival, the combination of fasting/FMD and vincristine promotes autophagy inhibition, which is at the center of the high toxicity phenotype specific to leukemia cells, possibly through a mechanism involving immune cells.Abstract Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.