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Background and purpose High arginase-1 (Arg) expression by myeloid-derived suppressor cells (MDSC) is known to inhibit antitumor T-cell responses through depletion of l -arginine. We have previously shown that nitric oxide (NO), an immune mediator produced from l -arginine, is a potent radiosensitizer of hypoxic tumor cells. This study therefore examines whether Arg + overexpressing MDSC may confer radioresistance through depleting the substrate for NO synthesis. Material and methods MDSC and Arg expression were studied in preclinical mouse CT26 and 4T1 tumor models and further validated in rectal cancer patients in comparison with healthy donors. The radioprotective effect of MDSC was analyzed in hypoxic tumor cells with regard to l -arginine depletion. Results In both mouse tumors and cancer patients, MDSC expansion was associated with Arg activation causing accelerated l -arginine consumption. l -Arginine depletion in turn profoundly suppressed the capacity of classically activated macrophages to synthesize NO resulting in impaired tumor cell radiosensitivity. In advanced cT3-4 rectal cancer, circulating neutrophils revealed Arg overexpression approaching that in MDSC, therefore mounting a protumor compartment wherein Arg + neutrophils increased from 17% to over 90%. Conclusions Protumor Arg + MDSC reveal a unique ability to radioprotect tumor cells through l -arginine depletion, a common mechanism behind both T-cell and macrophage inhibition. [ABSTRACT FROM AUTHOR]

Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways can potentially sensitize tumors with limited treatment options, such as triple-negative breast cancer (TNBC), to chemo- and/or radiotherapy. Dichloroacetate (DCA) is a specific inhibitor of the pyruvate dehydrogenase kinase (PDK), which leads to enhanced reactive oxygen species (ROS) production. ROS are the primary effector molecules of radiation and an increase hereof will enhance the radioresponse. In this study, we evaluated the effects of DCA and radiotherapy on two TNBC cell lines, namely EMT6 and 4T1, under aerobic and hypoxic conditions. As expected, DCA treatment decreased phosphorylated pyruvate dehydrogenase (PDH) and lowered both extracellular acidification rate (ECAR) and lactate production. Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells. Consistently, DCA radiosensitized hypoxic tumor cells and 3D spheroids while leaving the intrinsic radiosensitivity of the tumor cells unchanged. Our results suggest that although described as an oxidative phosphorylation (OXPHOS)-promoting drug, DCA can also increase hypoxic radioresponses. This study therefore paves the way for the targeting of mitochondrial metabolism of hypoxic cancer cells, in particular to combat radioresistance. [ABSTRACT FROM AUTHOR]