Abstract | PURPOSE: METHODS AND MATERIALS: Wild-type and MerTK-/- BALB/c mice were grafted in the flanks with CT26 tumors and treated with computed tomography guided RT. The role of macrophages and CD8 T cells in the response to radiation were demonstrated with cell depletion studies. The role of MerTK in priming immune responses after RT alone and with agonist antibodies to the T cell costimulatory molecule OX40 was evaluated in a Panc02-SIY model antigen system. The effect of warfarin therapy on the in-field and abscopal response to RT was demonstrated in murine models of colorectal adenocarcinoma. The association between warfarin and progression-free survival for patients treated with SABR for early-stage non-small cell lung cancer was evaluated in a multi-institutional retrospective study. RESULTS:
MerTK-/- hosts had better tumor control after RT compared with wild-type mice in a macrophage and CD8 T cell-dependent manner. MerTK-/- mice showed increased counts of tumor antigen-specific CD8 T cells in the peripheral blood after tumor-directed RT alone and in combination with agonist anti-OX40. Warfarin therapy phenocopied MerTK-/- for single-flank tumors treated with RT and improved abscopal responses for RT combined with anti-CTLA4. Patients on warfarin therapy when treated with SABR for non-small cell lung cancer had higher progression-free survival rates compared with non- warfarin users. CONCLUSIONS:
MerTK inhibits adaptive immune responses after SABR. Because warfarin inhibits MerTK signaling and phenocopies genetic deletion of MerTK in mice, warfarin therapy may have beneficial effects in combination with SABR and immune therapy in patients with cancer.
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Authors | Garth W Tormoen, Tiffany C Blair, Shelly Bambina, Gwen Kramer, Jason Baird, Ramtin Rahmani, John M Holland, Owen J T McCarty, Michael J Baine, Vivek Verma, Nima Nabavizadeh, Michael J Gough, Marka Crittenden |
Journal | International journal of radiation oncology, biology, physics
(Int J Radiat Oncol Biol Phys)
Vol. 108
Issue 1
Pg. 93-103
(09 01 2020)
ISSN: 1879-355X [Electronic] United States |
PMID | 32311417
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020 Elsevier Inc. All rights reserved. |
Chemical References |
- Warfarin
- c-Mer Tyrosine Kinase
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Topics |
- Adaptive Immunity
(genetics, radiation effects)
- Animals
- Cell Line, Tumor
- Gene Knockout Techniques
- Humans
- Mice
- Molecular Targeted Therapy
- Warfarin
(pharmacology, therapeutic use)
- c-Mer Tyrosine Kinase
(deficiency, genetics)
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