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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 27, 1999.The objective of this study was to elucidate the mechanisms by which nitric oxide (NO) inhibits rat aortic smooth muscle cell (

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 tumorbearing hosts, increased the number and function of tumorantigen-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 I͞II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.arginase ͉ immunosuppression ͉ myeloid cells ͉ nitric oxide ͉ immunotherapy I dentifying effective treatments for cancer is a clinical priority.Despite the plethora of evidence in preclinical models, the most advanced immunotherapy, either active or passive, has had limited success in human clinical trials (1). Basis for this conclusion appears to involve at least in part the progressive accumulation of myeloid cells, which exert a powerful inhibitory activity on antitumor lymphocytes as a function of tumor growth. In tumor-bearing hosts, for example, tumor progression is often associated with altered hematopoiesis, which leads to the accumulation of myeloid cells at the tumor site and in blood, secondary lymphoid organs, and bone marrow (2-4).Mouse myeloid cells express the CD11b and Gr-1 markers, have a mixed mature-immature myeloid phenotype, and are responsible for the induction of tumor-specific and nonspecific T cell dysfunctions, which are frequently observed not only in transplantable tumors but also in tumors spontaneously arising with transgenic expression of tissue-restricted oncogenes (2, 5). These cells have been termed myeloid suppressor cells (MSCs) and arise from bone marrow and other hematopoietic organs exposed to systemically released factors acting on myelomonocytic precursors (reviewed in refs. 2, 3, and 6). Moreover, MSCs are the final effectors of a circuit that negatively affects tumor immunity and that requires participation of natural killer T cells. Cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance was recently shown to be down-regulated by TGF-␤ released by CD11b ϩ ͞Gr-1 ϩ cells, an event driven by cytokine IL-13 release from CD1d-restricted natural killer T cells (7). This circuit is activated very early in tumor progression and ...

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