Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy.
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.
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.|The Oregon Clinic, Portland OR, USA.
Marka R
MR
Crittenden
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Jason
J
Baird
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
David
D
Friedman
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Talicia
T
Savage
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Lauren
L
Uhde
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Alejandro
A
Alice
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Benjamin
B
Cottam
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.|The Oregon Clinic, Portland OR, USA.
Kristina
K
Young
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.|Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, Portland OR, USA.
Pippa
P
Newell
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Cynthia
C
Nguyen
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Shelly
S
Bambina
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Gwen
G
Kramer
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Emmanuel
E
Akporiaye
Host-Tumour Interactions Group, Division of Cancer and Stem Cells, University of Nottingham, UK.
Anna
A
Malecka
Host-Tumour Interactions Group, Division of Cancer and Stem Cells, University of Nottingham, UK.
Andrew
A
Jackson
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland OR, USA.
Michael J
MJ
Gough
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D000067996:RAW 264.7 Cells; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000528:radiation effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D053961:Azabicyclo Compounds; D016207:Cytokines; D016328:NF-kappa B; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C528106:SM16 compound; D016212:Transforming Growth Factor beta; C490767:Mertk protein, mouse; D000076202:c-Mer Tyrosine Kinase
apoptosis; macrophage; phagocytosis; radiation; tumor