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Targeting COX-2 abrogates mammary tumorigenesis: Breaking cancer-associated suppression of immunosurveillance.

Markosyan N, Chen EP, Smyth EM - Oncoimmunology (2014)

Bottom Line: Three studies addressed the role of cyclooxygenase-2 (COX-2) in mammary tumorigenesis using epithelial and macrophage COX-2 knockout mice.Deletion of COX-2 in either cell restored, at least partially, tumor immunosurveillance either by changing macrophage function to offset pro-tumor effects, or by attracting more cytotoxic T lymphocytes and natural killer cells to the tumor.These studies suggest benefits from targeted COX-2 selective inhibition in combination with immunotherapies.

View Article: PubMed Central - PubMed

Affiliation: Institute for Translational Medicine and Therapeutics and Department of Pharmacology; University of Pennsylvania; Philadelphia, PA USA.

ABSTRACT
Three studies addressed the role of cyclooxygenase-2 (COX-2) in mammary tumorigenesis using epithelial and macrophage COX-2 knockout mice. Deletion of COX-2 in either cell restored, at least partially, tumor immunosurveillance either by changing macrophage function to offset pro-tumor effects, or by attracting more cytotoxic T lymphocytes and natural killer cells to the tumor. These studies suggest benefits from targeted COX-2 selective inhibition in combination with immunotherapies.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Cell-specific role of cyclooxygenase-2 (COX-2) in suppression of antitumor immune function. COX-2 in both tumor cells and macrophages may contribute to suppressed CTL function in mammary tumors. Tumor cell COX-2 may reduce expression of the T-cell attractant CXCL9, and enhance the lymphocyte co-inhibitory molecule PD-L1, thereby limiting lymphocyte infiltration and cytotoxic function. In addition, tumor cell COX-2 may skew macrophage polarization, limiting the antitumor pro-immune M1, and enhancing the pro-tumor immunosuppressive M2, phenotype. Macrophage COX-2 promotes CSF-1-dependent macrophage migration toward tumor cells as well as M2 polarization, thereby limiting the number and function of CTLs in tumors. TC = Tumor cell; mac = macrophage, M1 and M2 type; CTL = cytotoxic T cell; Th1 = helper T cell, type 1; NK = natural killer cell; CSF-1 = colony stimulating factor-1; CSF-1R = CSF-1 receptor; PGE2 = Prostaglandin E2; PD-L1 = programmed death-ligand 1.
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Figure 1: Figure 1. Cell-specific role of cyclooxygenase-2 (COX-2) in suppression of antitumor immune function. COX-2 in both tumor cells and macrophages may contribute to suppressed CTL function in mammary tumors. Tumor cell COX-2 may reduce expression of the T-cell attractant CXCL9, and enhance the lymphocyte co-inhibitory molecule PD-L1, thereby limiting lymphocyte infiltration and cytotoxic function. In addition, tumor cell COX-2 may skew macrophage polarization, limiting the antitumor pro-immune M1, and enhancing the pro-tumor immunosuppressive M2, phenotype. Macrophage COX-2 promotes CSF-1-dependent macrophage migration toward tumor cells as well as M2 polarization, thereby limiting the number and function of CTLs in tumors. TC = Tumor cell; mac = macrophage, M1 and M2 type; CTL = cytotoxic T cell; Th1 = helper T cell, type 1; NK = natural killer cell; CSF-1 = colony stimulating factor-1; CSF-1R = CSF-1 receptor; PGE2 = Prostaglandin E2; PD-L1 = programmed death-ligand 1.

Mentions: Immunosurveillance by CD8+ CTL and NK cells has emerged as critical for controlling nascent in situ tumor growth. This has led to a wave of promising new therapeutic strategies, including blockade of immune checkpoints such as CTLA-4, PD-L1, and its receptor PD-1, or adoptive transfer of anti-tumor T lymphocytes, with significant and durable clinical responses reported in trials.8,9 While the efficiency of COX-2 inhibition in promoting cytotoxic immune function should be verified in human breast and other cancers, our mouse studies implicate COX-2 in the ‘broken’ immune-surveillance that allows for mammary tumor progression (Fig. 1), and demonstrate that, rather than the hazardous systemic inhibition, targeted cell-specific COX-2 inhibition is sufficient to achieve the benefit. These studies open possibilities for combination of COX-2 inhibitors to potentiate the clinical effect of checkpoint blockade or adoptive T-cell transfer. Remarkably, our studies show that targeted inhibition of COX-2 in macrophages, a component of the complex tumor microenvironment, produced substantial antitumor immune function and suppressed tumor growth, revealing opportunities to combine targeted delivery of COX-2 selective inhibitors directly to macrophages. One approach is to incorporate coxibs into HDL nanoparticles, which are readily engulfed by macrophages,10 to achieve the tumor suppressive effect of systemic COX-2 inhibition but without thromboembolic risk, because COX-2 function in healthy vascular endothelium is spared. With such targeted strategies, the promise of COX-2 inhibitors in cancer prevention and therapy, which was all but lost to the cardiovascular risk of systemic inhibition, may be renewed and realized.


Targeting COX-2 abrogates mammary tumorigenesis: Breaking cancer-associated suppression of immunosurveillance.

Markosyan N, Chen EP, Smyth EM - Oncoimmunology (2014)

Figure 1. Cell-specific role of cyclooxygenase-2 (COX-2) in suppression of antitumor immune function. COX-2 in both tumor cells and macrophages may contribute to suppressed CTL function in mammary tumors. Tumor cell COX-2 may reduce expression of the T-cell attractant CXCL9, and enhance the lymphocyte co-inhibitory molecule PD-L1, thereby limiting lymphocyte infiltration and cytotoxic function. In addition, tumor cell COX-2 may skew macrophage polarization, limiting the antitumor pro-immune M1, and enhancing the pro-tumor immunosuppressive M2, phenotype. Macrophage COX-2 promotes CSF-1-dependent macrophage migration toward tumor cells as well as M2 polarization, thereby limiting the number and function of CTLs in tumors. TC = Tumor cell; mac = macrophage, M1 and M2 type; CTL = cytotoxic T cell; Th1 = helper T cell, type 1; NK = natural killer cell; CSF-1 = colony stimulating factor-1; CSF-1R = CSF-1 receptor; PGE2 = Prostaglandin E2; PD-L1 = programmed death-ligand 1.
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Figure 1: Figure 1. Cell-specific role of cyclooxygenase-2 (COX-2) in suppression of antitumor immune function. COX-2 in both tumor cells and macrophages may contribute to suppressed CTL function in mammary tumors. Tumor cell COX-2 may reduce expression of the T-cell attractant CXCL9, and enhance the lymphocyte co-inhibitory molecule PD-L1, thereby limiting lymphocyte infiltration and cytotoxic function. In addition, tumor cell COX-2 may skew macrophage polarization, limiting the antitumor pro-immune M1, and enhancing the pro-tumor immunosuppressive M2, phenotype. Macrophage COX-2 promotes CSF-1-dependent macrophage migration toward tumor cells as well as M2 polarization, thereby limiting the number and function of CTLs in tumors. TC = Tumor cell; mac = macrophage, M1 and M2 type; CTL = cytotoxic T cell; Th1 = helper T cell, type 1; NK = natural killer cell; CSF-1 = colony stimulating factor-1; CSF-1R = CSF-1 receptor; PGE2 = Prostaglandin E2; PD-L1 = programmed death-ligand 1.
Mentions: Immunosurveillance by CD8+ CTL and NK cells has emerged as critical for controlling nascent in situ tumor growth. This has led to a wave of promising new therapeutic strategies, including blockade of immune checkpoints such as CTLA-4, PD-L1, and its receptor PD-1, or adoptive transfer of anti-tumor T lymphocytes, with significant and durable clinical responses reported in trials.8,9 While the efficiency of COX-2 inhibition in promoting cytotoxic immune function should be verified in human breast and other cancers, our mouse studies implicate COX-2 in the ‘broken’ immune-surveillance that allows for mammary tumor progression (Fig. 1), and demonstrate that, rather than the hazardous systemic inhibition, targeted cell-specific COX-2 inhibition is sufficient to achieve the benefit. These studies open possibilities for combination of COX-2 inhibitors to potentiate the clinical effect of checkpoint blockade or adoptive T-cell transfer. Remarkably, our studies show that targeted inhibition of COX-2 in macrophages, a component of the complex tumor microenvironment, produced substantial antitumor immune function and suppressed tumor growth, revealing opportunities to combine targeted delivery of COX-2 selective inhibitors directly to macrophages. One approach is to incorporate coxibs into HDL nanoparticles, which are readily engulfed by macrophages,10 to achieve the tumor suppressive effect of systemic COX-2 inhibition but without thromboembolic risk, because COX-2 function in healthy vascular endothelium is spared. With such targeted strategies, the promise of COX-2 inhibitors in cancer prevention and therapy, which was all but lost to the cardiovascular risk of systemic inhibition, may be renewed and realized.

Bottom Line: Three studies addressed the role of cyclooxygenase-2 (COX-2) in mammary tumorigenesis using epithelial and macrophage COX-2 knockout mice.Deletion of COX-2 in either cell restored, at least partially, tumor immunosurveillance either by changing macrophage function to offset pro-tumor effects, or by attracting more cytotoxic T lymphocytes and natural killer cells to the tumor.These studies suggest benefits from targeted COX-2 selective inhibition in combination with immunotherapies.

View Article: PubMed Central - PubMed

Affiliation: Institute for Translational Medicine and Therapeutics and Department of Pharmacology; University of Pennsylvania; Philadelphia, PA USA.

ABSTRACT
Three studies addressed the role of cyclooxygenase-2 (COX-2) in mammary tumorigenesis using epithelial and macrophage COX-2 knockout mice. Deletion of COX-2 in either cell restored, at least partially, tumor immunosurveillance either by changing macrophage function to offset pro-tumor effects, or by attracting more cytotoxic T lymphocytes and natural killer cells to the tumor. These studies suggest benefits from targeted COX-2 selective inhibition in combination with immunotherapies.

No MeSH data available.


Related in: MedlinePlus