Cyclooxygenase inhibitors modulate NK activities that control metastatic disease.

Abstract

Cyclooxygenase (COX) inhibitors have demonstrated efficacy in models of human cancer but the relevant mechanisms have not all been elucidated. Both Cox-dependent as well as Cox-independent mechanisms have been implicated. Using a syngeneic model of metastatic breast cancer, we have investigated the effect of Cox inhibitors on NK functions that are critical to the control of metastatic disease. NK recognition of target cells is governed by a balance of activating and inhibiting receptors that bind ligands including MHC class I. We now show that treatment of tumor cells with the nonselective COX-1/COX-2 inhibitor indomethacin or the selective COX-2 inhibitor celecoxib leads to decreased expression of the MHC class I molecules Ld and Kd . Downregulated class I expression is associated with concomitant increased sensitivity to NK cell-mediated lysis. Both COX inhibitors limit tumor metastasis and this therapeutic effect is dependent on NK but not T cell function. Antimetastatic activity is also lost in the absence of interferon- gamma (IFN-gamma). Both COX inhibitors also suppress local tumor growth of subcutaneously implanted mammary tumor cells in immune competent Balb/cByJ mice. This therapeutic activity is lost in the absence of either CD4+ or CD8+ T cells, but is not compromised by the loss of NK activity. Thus, the mechanism of tumor inhibition differs in the context of local versus metastatic disease. Taken together, these findings are consistent with a mechanism not previously described, whereby COX inhibitors may relieve MHC-mediated inhibition of NK cytotoxicity leading to recognition and lysis of metastatic tumor cells.

• Authors: Namita Kundu, Tonya C Walser, Xinrong Ma, Amy M Fulton
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 54 Issue 10 Pg. 981-7 (Oct 2005) ISSN: 0340-7004 [Print] Germany
• PMID: 15891886 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Histocompatibility Antigens Class I
• Membrane Proteins
• Pyrazoles
• Sulfonamides
• Interferon-gamma
• Cyclooxygenase 1
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Ptgs1 protein, mouse
• Celecoxib
• Indomethacin

Topics

• Animals
• Celecoxib
• Cyclooxygenase 1
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Cytotoxicity, Immunologic (drug effects)
• Down-Regulation
• Female
• Histocompatibility Antigens Class I (chemistry, metabolism)
• Indomethacin (pharmacology)
• Interferon-gamma (genetics, physiology)
• Killer Cells, Natural (immunology)
• Mammary Neoplasms, Experimental (drug therapy, immunology, secondary)
• Membrane Proteins
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Prostaglandin-Endoperoxide Synthases (chemistry)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)