Nitroaspirin Corrects Immune Dysfunction in Tumor-Bearing Hosts and Promotes Tumor Eradication by Cancer Vaccination

Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of system...

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Published in	Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 11; pp. 4185 - 4190
Main Authors	De Santo, Carmela, Serafini, Paolo, Marigo, Ilaria, Dolcetti, Luigi, Bolla, Manlio, Del Soldato, Piero, Melani, Cecilia, Guiducci, Cristiana, Colombo, Mario P., Iezzi, Manuela, Musiani, Piero, Zanovello, Paola, Bronte, Vincenzo, Ignarro, Louis J.
Format	Journal Article
Language	English
Published	United States National Academy of Sciences 15.03.2005 National Acad Sciences
Subjects	Amino acids Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Aspirin - analogs & derivatives Aspirin - pharmacology Biological Sciences Cancer Cancer Vaccines - pharmacology Carrier Proteins Cell lines Clinical trials Enzymatic activity Enzymes Immune status Immune system Immune System Diseases - drug therapy Immune System Diseases - immunology Lipocalins Lymphocytes Mice Mice, Inbred BALB C Molecules Myeloid cells Neoplasm Proteins Neoplasms - drug therapy Neoplasms - immunology Neoplasms - mortality Nitric oxide Nitric Oxide Synthase - metabolism Pharmacology Splenocytes T lymphocytes T-Lymphocytes - drug effects T-Lymphocytes - immunology Time Factors Tumor cell line Tumors Vaccination Vaccines
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ISSN	0027-8424 1091-6490 1091-6490
DOI	10.1073/pnas.0409783102

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Summary:	Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I/II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.
Bibliography:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-2 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Present address: The Johns Hopkins University, Baltimore, MD 21231. Abbreviations: ARG, arginase; MSC, myeloid suppressor cell; TET, Ld H-2 tetramer; MLR, mixed leukocyte reaction; NOS, NO synthase; CTL, cytotoxic T lymphocyte; l-NMMA, Ng-monomethyl-l-arginine; l-norv, l-norvaline. Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved February 1, 2005 This paper was submitted directly (Track II) to the PNAS office. Author contributions: P.Z. and V.B. designed research; C.D.S., P.S., I.M., L.D., C.M., and M.I. performed research; C.D.S., P.S., P.D.S., M.P.C., P.M., P.Z., and V.B. analyzed data; M.B., P.D.S., and C.G. contributed new reagents/analytic tools; and C.D.S., M.P.C., P.M., and V.B. wrote the paper. To whom correspondence should be addressed at: Department of Oncology and Surgical Science, Oncology Section, Padua University, Via Gattamelata 64, 35128 Padua, Italy. E-mail: enzo.bronte@unipd.it. C.D.S. and P.S. contributed equally to this work.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.0409783102