Abstract
Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFβ inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy.
Keywords:
apoptosis; macrophage; phagocytosis; radiation; tumor.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Azabicyclo Compounds / pharmacology
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Cell Line, Tumor
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Coculture Techniques
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Cytokines / metabolism
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Macrophages / enzymology
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Macrophages / immunology
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Macrophages / pathology
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Macrophages / radiation effects*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism
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Neoplasm Recurrence, Local*
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Neoplasms, Experimental / enzymology
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / pathology
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Neoplasms, Experimental / radiotherapy*
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RAW 264.7 Cells
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / metabolism
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / radiation effects
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Time Factors
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Transforming Growth Factor beta / metabolism
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c-Mer Tyrosine Kinase / antagonists & inhibitors
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c-Mer Tyrosine Kinase / deficiency
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c-Mer Tyrosine Kinase / genetics
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c-Mer Tyrosine Kinase / metabolism*
Substances
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Azabicyclo Compounds
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Cytokines
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NF-kappa B
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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SM16 compound
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Transforming Growth Factor beta
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Mertk protein, mouse
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c-Mer Tyrosine Kinase