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Cyclooxygenase inhibitors modulate NK activities that control metastatic disease
Namita Kundu1, Tonya C Walser, Xinrong Ma
1Department of Pathology, University of Maryland, 10 S. Pine St, Baltimore, MD 21201, USA.
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.
Insights
Cyclooxygenase (COX) inhibitors reduce breast cancer metastasis by decreasing MHC class I on tumor cells, enhancing natural killer (NK) cell activity. This mechanism, dependent on interferon-gamma (IFN-γ), differs from their effect on local tumor growth.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Cyclooxygenase (COX) inhibitors show promise in cancer treatment, but their precise mechanisms, including both COX-dependent and independent pathways, remain incompletely understood.
- Natural killer (NK) cell activity is crucial for controlling metastatic disease, with target cell recognition influenced by the balance of activating and inhibiting receptors, including those binding to MHC class I molecules.
Purpose of the Study:
- To investigate the effects of COX inhibitors on NK cell functions in a syngeneic model of metastatic breast cancer.
- To elucidate the mechanisms by which COX inhibitors impact tumor metastasis and local tumor growth, differentiating between NK and T cell involvement.
Main Methods:
- Treatment of breast tumor cells with nonselective (indomethacin) and selective (celecoxib) COX inhibitors.
- Assessment of MHC class I expression on tumor cells and sensitivity to NK cell-mediated lysis.
- Evaluation of therapeutic effects on metastasis and local tumor growth in immunocompetent mice, utilizing knockout models for NK cells, CD4+ T cells, CD8+ T cells, and interferon-gamma (IFN-γ).
Main Results:
- COX inhibitors significantly decreased MHC class I expression (Ld and Kd) on tumor cells, increasing their susceptibility to NK cell lysis.
- Both indomethacin and celecoxib limited tumor metastasis, an effect dependent on NK cell activity and interferon-gamma (IFN-γ), but not T cells.
- COX inhibitors suppressed local tumor growth, an effect dependent on CD4+ and CD8+ T cells, but independent of NK cell activity.
Conclusions:
- COX inhibitors may exert antimetastatic effects by downregulating MHC class I on tumor cells, thereby disinhibiting NK cell cytotoxicity.
- The therapeutic mechanisms of COX inhibitors differ between controlling local tumor growth (T cell-dependent) and preventing metastasis (NK cell-dependent).
- These findings reveal a novel mechanism for COX inhibitor action in cancer therapy, highlighting their role in modulating anti-tumor immune responses.
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