Garth W Tormoen1, Tiffany C Blair2, Shelly Bambina3, Gwen Kramer3, Jason Baird3, Ramtin Rahmani4, John M Holland4, Owen J T McCarty5, Michael J Baine6, Vivek Verma7, Nima Nabavizadeh4, Michael J Gough3, Marka Crittenden8. 1. Department of Radiation Medicine, Oregon Health & Science University, Portland, OR. Electronic address: tormoeng@ohsu.edu. 2. Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR. 3. Earl A. Chiles Research Institute, Providence Medical Center, Portland, OR. 4. Department of Radiation Medicine, Oregon Health & Science University, Portland, OR. 5. Department of Biomedical Engineering, School of Medicine, Oregon Health & Sciences University, Portland, OR; Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Sciences University, Portland, Oregon. 6. Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. 7. Department of Radiation Oncology, Alleghany General Hospital, Pittsburgh, Pennsylvania. 8. Earl A. Chiles Research Institute, Providence Medical Center, Portland, OR; The Oregon Clinic, Portland, Oregon.
Abstract
PURPOSE: The role of MerTK, a member of the Tyro3-Axl-MerTK family of receptor tyrosine kinase, in the immune response to radiation therapy (RT) is unclear. We investigated immune-mediated tumor control after RT in murine models of colorectal and pancreatic adenocarcinoma using MerTK wild-type and knock-out hosts and whether inhibition of MerTK signaling with warfarin could replicate MerTK knock-out phenotypes. 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.
PURPOSE: The role of MerTK, a member of the Tyro3-Axl-MerTK family of receptor tyrosine kinase, in the immune response to radiation therapy (RT) is unclear. We investigated immune-mediated tumor control after RT in murine models of colorectal and pancreatic adenocarcinoma using MerTK wild-type and knock-out hosts and whether inhibition of MerTK signaling with warfarin could replicate MerTK knock-out phenotypes. METHODS AND MATERIALS: Wild-type and MerTK-/- BALB/c mice were grafted in the flanks with CT26tumors 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.
Authors: Shawn M Jensen; Levi D Maston; Michael J Gough; Carl E Ruby; William L Redmond; Marka Crittenden; Yuhuan Li; Sachin Puri; Christian H Poehlein; Nick Morris; Magdalena Kovacsovics-Bankowski; Tarsem Moudgil; Chris Twitty; Edwin B Walker; Hong-Ming Hu; Walter J Urba; Andrew D Weinberg; Brendan Curti; Bernard A Fox Journal: Semin Oncol Date: 2010-10 Impact factor: 4.929
Authors: Muhammad S Beg; Arjun Gupta; David Sher; Sadia Ali; Saad Khan; Ang Gao; Tyler Stewart; Chul Ahn; Jarett Berry; Eric M Mortensen Journal: Am J Clin Oncol Date: 2018-08 Impact factor: 2.339
Authors: Jingying Xu; Jemima Escamilla; Stephen Mok; John David; Saul Priceman; Brian West; Gideon Bollag; William McBride; Lily Wu Journal: Cancer Res Date: 2013-02-15 Impact factor: 12.701
Authors: Michael J Gough; Marka R Crittenden; MaryClare Sarff; Puiyi Pang; Steven K Seung; John T Vetto; Hong-Ming Hu; William L Redmond; John Holland; Andrew D Weinberg Journal: J Immunother Date: 2010-10 Impact factor: 4.456
Authors: L R Zacharski; W G Henderson; F R Rickles; W B Forman; C J Cornell; R J Forcier; R L Edwards; E Headley; S H Kim; J F O'Donnell Journal: Cancer Date: 1984-05-15 Impact factor: 6.860
Authors: Youjin Lee; Sogyong L Auh; Yugang Wang; Byron Burnette; Yang Wang; Yuru Meng; Michael Beckett; Rohit Sharma; Robert Chin; Tony Tu; Ralph R Weichselbaum; Yang-Xin Fu Journal: Blood Date: 2009-04-06 Impact factor: 22.113
Authors: Magdalena Paolino; Axel Choidas; Stephanie Wallner; Blanka Pranjic; Iris Uribesalgo; Stefanie Loeser; Amanda M Jamieson; Wallace Y Langdon; Fumiyo Ikeda; Juan Pablo Fededa; Shane J Cronin; Roberto Nitsch; Carsten Schultz-Fademrecht; Jan Eickhoff; Sascha Menninger; Anke Unger; Robert Torka; Thomas Gruber; Reinhard Hinterleitner; Gottfried Baier; Dominik Wolf; Axel Ullrich; Bert M Klebl; Josef M Penninger Journal: Nature Date: 2014-02-19 Impact factor: 49.962
Authors: Yemsratch T Akalu; Maria E Mercau; Marleen Ansems; Lindsey D Hughes; James Nevin; Emily J Alberto; Xinran N Liu; Li-Zhen He; Diego Alvarado; Tibor Keler; Yong Kong; William M Philbrick; Marcus Bosenberg; Silvia C Finnemann; Antonio Iavarone; Anna Lasorella; Carla V Rothlin; Sourav Ghosh Journal: Elife Date: 2022-08-15 Impact factor: 8.713