Effects of Indomethacin on Lymphokine-Activated Killer Cell Activities in Cancer Patients

Abstract

Prostaglandin E₂ (PGE₂) is known to downregulate the generation of lymphokine-activated killer (LAK) cell activity. Indomethacin, an inhibitor of cyclooxygenase catalyzing the biosynthesis of PGE₂, has been shown to augment LAK cell activities generated from peripheral blood mononuclear cells of normal healthy individuals. This study was undertaken to examine whether or not this augmentation is also a common phenomenon in cancer patients. LAK cell activities generated in the presence and the absence of indomethacin were examined in 15 normal healthy individuals and in 83 cancer patients. Paired data analysis revealed that indomethacin exhibited a significant augmentation of LAK activity generated from healthy individuals. Indomethacin enhanced LAK activity in patients with no distant metastases (T_xN_xM₀); but depressed LAK activity in patients with distant metastases (T_xN_xM₁). In patients without distant metastases, indomethacin showed an upregulating effect on LAK activity in those with an early T stage (T_1-2N_xM₀), and no such effect was detected in those with a late T stage (T_3-4N_xM₀). Indomethacin also significantly enhanced LAK cell generation in cancer patients with an ECOG performance status of 1, but significantly inhibited LAK cell generation in patients with a performance status of 4. These results indicated that indomethacin inhibited generation of LAK cell activity in cancer patients with a poor performance status or with distant metastatic disease, who normally would be the subjects of adoptive immunotherapy. Further, PGE₂ production in cultured LAK cell medium was suppressed by indomethacin in all 20 cancer patients that were examined, suggesting that other yet to be identified factors or mechanisms may be responsible for the paradoxical effects of indomethacin on LAK cell activity.

Comparison of the Effects of Immunosuppressive Factors from Newly Established Colon Carcinoma Cell Cultures on Human Lymphocyte Proliferation and Cytokine Secretion

“…Elevated PGE 2 levels were observed both in vivo and in the supernatants of cultured tumor cell lines, but elevated values could be prevented by the administration of indomethacin [9]. Furthermore, also the inhibition of LAK cell generation in vitro and an impaired NK cell activity by PGE 2 can be reversed in a tumor-bearing host by the administration of indomethacin [20]. Our data corroborate the notion that PGE 2 may be involved in immunosuppression in some tumor patients.…”

Cyclooxygenase-2 Inhibition Augments the Hepatic Antitumor Effect of Oral Salmonella Typhimurium in a Model of Mouse Metastatic Colon Cancer

“…14,15 PGE2 is elevated in the setting of COX2 expression and leads to impaired lymphokine activated killing by T cells. 16 Inhibiting COX2 has been associated with restoring impaired lymphokine activated killing and immune surveillance. 16 Interestingly, COX2i has recently been implicated as being T-cell immunosuppressive, 17 and, therefore, the potential immunomodulating capacities of COX2i are still being elucidated.…”

“…16 Inhibiting COX2 has been associated with restoring impaired lymphokine activated killing and immune surveillance. 16 Interestingly, COX2i has recently been implicated as being T-cell immunosuppressive, 17 and, therefore, the potential immunomodulating capacities of COX2i are still being elucidated. Finally, preliminary evidence also documents that COX2 selective inhibitors can cause apoptosis in cancer cell lines, suggesting that a potential mechanism for their action may be through induction of apoptosis and inhibition of cellular proliferation.…”

“…Iniguez et al 17 recently reported convincing in vitro evidence that COX2i is T-cell immunosuppressive. Conversely, Chao et al 16 argued that COX inhibitors could restore immune surveillance that had been inhibited by PGE2 (generated through COX2). In our current experiments, we aimed to discern what affect, if any, COX2i may be having on hepatic CD4 ϩ , CD8 ϩ , or NK1.1 ϩ CD4 Ϫ lymphocytes.…”