Expression of Cationic Amino Acid Transporter 2 Is Required for Myeloid-Derived Suppressor Cell-Mediated Control of T Cell Immunity.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells that expand during benign and cancer-associated inflammation and are characterized by their ability to inhibit T cell immunity. Increased metabolism of l-Arginine (l-Arg), through the enzymes arginase 1 and NO synthase 2 (NOS2), is well documented as a major MDSC suppressive mechanism. Therefore, we hypothesized that restricting MDSC uptake of l-Arg is a critical control point to modulate their suppressor activity. Using murine models of prostate-specific inflammation and cancer, we have identified the mechanisms by which extracellular l-Arg is transported into MDSCs. We have shown that MDSCs recruited to localized inflammation and tumor sites upregulate cationic amino acid transporter 2 (Cat2), coordinately with Arg1 and Nos2. Cat2 expression is not induced in MDSCs in peripheral organs. CAT2 contributes to the transport of l-Arg in MDSCs and is an important regulator of MDSC suppressive function. MDSCs 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 low intracellular l-Arg levels, which leads to the impaired ability of NOS2 to catalyze l-Arg-dependent metabolic processes. Together, these findings demonstrate that CAT2 modulates MDSC function. In the absence of CAT2, MDSCs display diminished capacity for controlling T cell immunity in prostate inflammation and cancer models, where the loss of CAT2 results in enhanced antitumor activity.
Comparative Pathobiology Department, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907; and.
Cansu
C
Cimen Bozkus
Comparative Pathobiology Department, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907; and.
Bennett D
BD
Elzey
Comparative Pathobiology Department, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907; and.
Scott A
SA
Crist
Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
Lesley G
LG
Ellies
Comparative Pathobiology Department, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907; and tlratliff@purdue.edu.
Timothy L
TL
Ratliff
D026923:Amino Acid Transport Systems, Basic / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D001120:Arginine / Q000378:metabolism; D001692:Biological Transport; D027202:Cationic Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D026923:Amino Acid Transport Systems, Basic; D027202:Cationic Amino Acid Transporter 2; D017382:Reactive Oxygen Species; C087435:Slc7a2 protein, mouse; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase