title: Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.
abstract: 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.
authors.affiliation: Department of Oncology and Surgical Sciences, University of Padova, 35100 Padova, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.forename: Tihana
authors.initials: T
authors.lastname: Kasic
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gri
authors.forename: Keti
authors.initials: K
authors.lastname: Gallana
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marigo
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Massimo
authors.initials: M
authors.lastname: Iafrate
authors.forename: Tommaso
authors.initials: T
authors.lastname: Prayer-Galetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Pagano
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
mesh_terms: 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
chemical_list: C002744:3-nitrotyrosine; D014443:Tyrosine; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase