L-Arginine depletion blunts anti-tumor T cell responses by inducing myeloid-derived suppressor cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-11, Vol.75 (2), p.275-283
• Main Authors: Fletcher, Matthew, Ramirez, Maria E., Sierra, Rosa A., Raber, Patrick, Thevenot, Paul, Al-Khami, Amir A., Sanchez-Pino, Dulfary, Hernandez, Claudia, Wyczechowska, Dorota D., Ochoa, Augusto C., Rodriguez, Paulo C.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-1491

Enzymatic depletion of the non-essential amino acid L-Arginine (L-Arg) in cancer patients by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, L-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T-cells. Strikingly, we found that peg-Arg I blocked proliferation and cell cycle progression in normal activated T-cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T-cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T-cells exposed to peg-Arg I. Further mechanistic investigations showed that addition of citrulline, a metabolic precursor for L-Arg, rescued the anti-proliferative effects of peg-Arg I on T-cells in vitro . Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo , peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control non-repressed-2 eIF2α kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the L-Arg-depleting therapy for cancer treatment and suggest a need for co-targeting MDSC in such therapeutic settings.