Myeloid-derived suppressor cells reveal radioprotective properties through arginase-induced l-arginine depletion. Issue 2 (May 2016)

• Record Type: Journal Article
• Authors: Leonard, Wim; Dufait, Inès; Schwarze, Julia Katharina; Law, Kalun; Engels, Benedikt; Jiang, Heng; Van den Berge, Dirk; Gevaert, Thierry; Storme, Guy; Verovski, Valeri; Breckpot, Karine; De Ridder, Mark
• Is Part Of: Radiotherapy and oncology. Volume 119:Issue 2(2016:May)
• Page Start: 291
• Page End: 299
• Publication Date: 2016-05
• Subjects: MDSC -- Arginase -- l-Arginine -- Hypoxic radiosensitivity -- Rectal cancer; Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2016.01.014
• Languages: English
• ISSNs: 0167-8140

Abstract

Abstract: Background and purpose: High arginase-1 (Arg) expression by myeloid-derived suppressor cells (MDSC) is known to inhibit antitumor T-cell responses through depletion ofl -arginine. We have previously shown that nitric oxide (NO), an immune mediator produced froml -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 tol -arginine depletion. Results: In both mouse tumors and cancer patients, MDSC expansion was associated with Arg activation causing acceleratedl -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 throughl -arginine depletion, a common mechanism behind both T-cell and macrophage inhibition.