Polyamine deprivation prevents the development of tumour-induced immune suppression

Abstract

Summary Mice grafted with the 3LL (Lewis lung) carcinoma exhibit immune suppression: spleen cells showed decreased spontaneous interleukin 2 (IL-2) production and T-CD4+ and T-CD8+ lymphocyte populations; in addition the polyamine content in the spleen was increased. By treating the mice with a polyamine-deficient diet containing neomycin, metronidazole and inhibitors of ornithine decarboxylase and polyamine oxydase, tumour growth was reduced and the immune abnormalities were reversed. The spleen cells overproduced IL-2 by reducing exogenous sources of polyamines, but total blockade of all major polyamine sources was necessary to obtain an optimal effect both on IL-2 production and on spleen polyamine content. Irrespective of whether polyamine deprivation was started at an early or at an advanced stage of tumour growth, T-lymphocyte populations were restored to normal values, demonstrating that polyamine deprivation not only prevents tumour-induced immune suppression, but reverses established immunological disorders. In contrast to what was observed regarding IL-2 production by spleen cells and natural killer (NK) cell activity, the polyamine oxidase (PAO) inhibitor did not enhance the number of T lymphocytes. These findings are consistent with a direct effect of the polyamines on immune effector cell metabolism. They suggest an important role of the gastrointestinal polyamines and of PAO activity in the regulation of IL-2 production.

Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression

“…Indeed, polyamines (via the arginine-ornithine-polyamine axis) contribute to a tumor-permissive microenvironment through myriad effects on immunosurveillance mechanisms (57)(58)(59), so efforts to study polyamine depletion in this context are warranted. Indeed, COX activity in tumors contributes to immune evasion and biochemical inhibition of these pathways restores antitumor immunity (60), providing an additional potential mechanism for the enhanced antitumor activities seen with DFMO and celecoxib in our models.…”

Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

“…In recent years several groups have described defective immune function in tumour-bearing animals [18,20,21] and in cancer patients [8,22,23]. Of note, it was reported that factors produced by tumour cells could influence differentiation of DCs from CD34 + progenitors, and that low concentrations of IL-4 could reverse the inhibitory effect of cancer cell conditioned medium, at least in terms of phenotype and some functional differentiation of DCs [22].…”

“…However, the role played by polyamines in immune processes is poorly understood [16,17]. Nevertheless, our group showed that polyamine deprivation can prevent the development of in vivo tumour-induced immunosuppression [18]. In the present study, the hypothesis that putrescine is involved in immunodeficiency was tested by investigating the effects of putrescine on functional activity of DCs from donors.…”

Immunosuppresive Factors in Cancer

“…These data suggest that polyamines are immunostimulating for T cells. In addition, polyamine deprivation in animals grafted with Lewis lung carcinoma tumors reverses tumor-induced immunosuppression (decreased splenic IL-2 production, and depressed levels of CD4 + and CD8 + T cell populations), but is not associated with any changes in host CTL activity [305].…”

“…Inhibition of polyamine biosynthesis and polyamine deprivation in vivo is associated with decreased tumor growth and metastases and significantly enhanced NK cytotoxic activity [267,306]. Thus, polyamines are inhibitory for NK cells.…”