Expression of cationic amino acid transporter 2 is required for myeloid derived suppressor cell-mediated control of T cell immunity (IRC4P.460)

Abstract

Abstract Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature cells that expand during benign and cancer-associated inflammation. MDSC regulate innate and adaptive immunity, notably by inhibiting T cell functions. Increased metabolism of L-Arginine (L-Arg), through arginase 1 (ARG1) and nitric oxide synthase 2 (NOS2), is well documented as a major MDSC suppressive mechanism. However, the mechanism by which extracellular L-Arg is transported into MDSC is not defined. Using murine models of prostate specific inflammation and cancer, we show that MDSC recruited to localized inflammation and tumor sites upregulate cationic amino acid transporter 2 (Cat2) coordinately with Arg1 and Nos2. CAT2 contributes to the transport of L-Arg in MDSC and acts as an important regulator of MDSC suppressive function. MDSC that lack CAT2 have significantly reduced suppressive ability ex vivo and display impaired capacity for regulating T cell responses in vivo as evidenced by increased T cell expansion and decreased tumor growth in Cat2-/- mice. The abrogation of suppressive function is due to lower L-Arg uptake, which leads to the impaired ability of NOS2 to catalyze L-Arg metabolic processes. These findings demonstrate that CAT2 is an important regulator of MDSC suppressive function. In the absence of CAT2 MDSC display diminished capacity for controlling T cell immunity in prostate inflammation and cancer models, where the loss of CAT2 results in enhanced antitumor activity.