Modulators of arginine metabolism do not impact on peripheral T-cell tolerance and disease progression in a model of spontaneous prostate cancer.
OBJECTIVE
Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b(+)Gr1(+) cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.


METHODS
Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, L-NAME or sildenafil, and evaluated for CD11b(+) cells accumulation in the blood, several organs, and the tumor mass and for disease progression.


RESULTS
CD11b(+)Gr1(high), CD11b(+)Gr1(int), and CD11b(+)Gr1(-) cells differently accumulated in different organs and especially in the tumor of the two mouse models. L-NAME and sildenafil impaired the immunosuppressive function of CD11b(+) cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice.


CONCLUSIONS
Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance.
PIBIC, Department of Immunology Infectious Diseases and Transplantation, Istituto Scientifico San Raffaele, Milan, Italy.
Nicolò
N
Rigamonti
Giusy
G
Capuano
Alessia
A
Ricupito
Elena
E
Jachetti
Matteo
M
Grioni
Luca
L
Generoso
Massimo
M
Freschi
Matteo
M
Bellone
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D039481:CD11b Antigen; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D007108:Immune Tolerance / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D038042:Myelopoiesis; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D039481:CD11b Antigen; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D001120:Arginine; D000068677:Sildenafil Citrate; D019331:NG-Nitroarginine Methyl Ester