Interleukin-2 (IL-2) Augments the Expression of Transforming Growth Factor Beta in Patients with Disseminated Cancer

Interleukin-2 (IL-2), originally discovered in the supernatant of lectin or antigen-stimulated T-cell cultures1-2, possesses a panoply of immunologic effects such as induction of paracrine growth of antigen-stimulated T-lymphocytes and of non-MHC restricted antitumor cytotoxic activity3-5. The mechanism involved in IL-2-induced signal transduction leading to these effects remains to be resolved6. The production of recombinant IL-2 has allowed the exploration of its biological effects as well as its therapeutic potential as an antitumor agent. Clinical Phase I and II studies of IL-2 in patients with disseminated cancer have shown that the lymphokine alone is able to induce often impressive regression of tumors typically insensitive to chemotherapy or radiation therapy7-10. Administration of IL-2 at tumoricidal doses, however, causes severe and limiting toxic side effects that often preclude its administration. Thrombocytopenia is universal toxicity of IL-2 therapy: it is not consequent to decreased marrow production but to peripheral sequestration of platelets11 and it is accompanied, in vitro12 and in vivo, by platelet degranulation (Paciucci, unpublished data) mediated by the release of thromboxan A-2 from IL-2-activated mononuclear cells in vitro12 and, perhaps, in vivo. Systemic platelet degranulation, in turn, is responsible for high circulating levels of other factors contained in alpha granules (such as PF-4 and beta thromboglobulin). Interestingly, PF-4 has recently been shown to have in vivo antitumoral effects through inhibition of tumor neovascularization13,14.