Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.
Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.
Bronte
Vincenzo
V
Department of Oncology and Surgical Sciences, University of Padova, 35100 Padova, Italy.
Kasic
Tihana
T
Gri
Giorgia
G
Gallana
Keti
K
Borsellino
Giovanna
G
Marigo
Ilaria
I
Battistini
Luca
L
Iafrate
Massimo
M
Prayer-Galetti
Tommaso
T
Pagano
Francesco
F
Viola
Antonella
A
D000230:Adenocarcinoma / Q000097:blood / Q000201:enzymology / Q000276:immunology*; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000037:antagonists & inhibitors / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009924:Organ Culture Techniques; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
C002744:3-nitrotyrosine; D014443:Tyrosine; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase