Modulators of arginine metabolism support cancer immunosurveillance.
BACKGROUND
Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity.


RESULTS
We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.


CONCLUSIONS
Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.
Capuano
Giusy
G
Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milan, Italy. giusy_capuano@hotmail.com
Rigamonti
Nicolò
N
Grioni
Matteo
M
Freschi
Massimo
M
Bellone
Matteo
M
D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007155:Immunologic Factors / Q000378:metabolism*; D007157:Immunologic Surveillance / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000473:pathology; D038042:Myelopoiesis / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D015431:Weight Loss / Q000187:drug effects
D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D007371:Interferon-gamma; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester