Immune modulatory effects of indomethacin in melanoma patients are not related to prostaglandin E₂-mediated suppression

Indomethacin significantly enhances the depressed levels of lymphocyte proliferation to the mitogens phytohemagglutinin and concanavalin A in melanoma patients. We postulated that these results were related to an abnormality in prostaglandin E₂ (PGE₂)-mediated suppression, since this mechanism has previously been demonstrated in patients with Hodgkin's lymphoma and with head and neck carcinoma. However, the results of three experimental approaches did not support this hypothesis. First, in vitro PGE₂ production by cultured blood mononuclear cells was the same in 16 melanoma patients as in 45 normal controls (4.9 versus 4.7 ng/ml). Second, lymphocyte sensitivity to PGE₂ for melanoma patient was essentially the same as that for normal controls, since exogenous doses of PGE₂ inhibited the mitogen responses to the same degree. Third, another prostaglandin synthetase inhibitor (RO-205720), which is structurally unrelated to indomethacin, did not augment the mitogen response in these patients. Thus PGE₂ cannot be implicated as a mediator of immunosuppression in melanoma patients. To further examine the immunomodulatory mechanism of indomethacin, we preincubated the drug with purified populations of either lymphocytes or monocytes, which were then recombined and tested for mitogen response. The results suggested that indomethacin had a direct effect on the responding T lymphocytes rather than an indirect effect on monocytes. These are the first studies demonstrating that indomethacin can act directly as a modulator of cellular immune function, independent of PGE₂-mediated suppression.