The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 11 April 2005 doi:10.1084/jem.20042028
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 8, 1257-1268
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ARTICLE

 Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

Vincenzo Bronte1, Tihana Kasic4, Giorgia Gri4, Keti Gallana4, Giovanna Borsellino5, Ilaria Marigo1, Luca Battistini5, Massimo Iafrate2, Tommaso Prayer-Galetti2, Francesco Pagano2,4, and Antonella Viola3,4

1 Department of Oncology and Surgical Sciences, University of Padova
2 Department of Urology, University of Padova
3 Department of Biomedical Sciences, University of Padova
4 Venetian Institute of Molecular Medicine, 35100 Padova, Italy
5 Neuroimmunology Unit, Santa Lucia Foundation Scientific Institute IRCCS, 00143 Rome, Italy

CORRESPONDENCE Antonella Viola: antonella.viola{at}unipd.it

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.

Abbreviations used: ARG, arginase; L-Arg, L-arginine; L-NMMA, N-monomethyl- L-arginine; NO, nitric oxide; NOHA, N-hydroxy-L-arginine; NOS, nitric oxide synthase; PCa, prostate carcinoma; TIA-1, T cell intracellular antigen 1; TIL, tumor-infiltrating lymphocytes; TRAMP, transgenic adenocarcinoma mouse prostate.


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