TY - JOUR
T1 - Key role for neutrophils in radiation-induced antitumor immune responses
T2 - Potentiation with G-CSF
AU - Takeshima, Tsuguhide
AU - Pop, Laurentiu M.
AU - Laine, Aaron
AU - Iyengar, Puneeth
AU - Vitetta, Ellen S.
AU - Hannan, Raquibul
N1 - Funding Information:
We thank Dr. Hak Choy for funding and advice; Drs. Debabrata Saha, Michael Story, Hasan Zaki, Jeffrey Meyer, and Yang-Xin Fu for their advice; Dr. R. Thompson for providing the RM-9 cell line; Suneetha Eluru for her assistance on assays; and Dr. Damiana Chiavolini for editing our manuscript. We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for providing the H-2Kb OVA-tetramer. We also thank the Flow Cytometry, Molecular Pathology, Animal Resource Center, and Genomics and Microarray Cores at the University of Texas Southwestern Medical Center. Research reported in this publication was supported by grants from the Department of Radiation Oncology, the University of Texas Southwestern Medical Center; the Cancer Immunobiology Center; the Simmons Patigian Chair; and the Horchow Foundation (E.S.V.).
Publisher Copyright:
© 2016, National Academy of Sciences. All rights reserved.
PY - 2016/10/4
Y1 - 2016/10/4
N2 - Radiation therapy (RT), a major modality for treating localized tumors, can induce tumor regression outside the radiation field through an abscopal effect that is thought to involve the immune system. Our studies were designed to understand the early immunological effects of RT in the tumor microenvironment using several syngeneic mouse tumor models. We observed that RT induced sterile inflammation with a rapid and transient infiltration of CD11b+Gr-1high+ neutrophils into the tumors. RT-recruited tumor-associated neutrophils (RT-Ns) exhibited an increased production of reactive oxygen species and induced apoptosis of tumor cells. Tumor infiltration of RT-Ns resulted in sterile inflammation and, eventually, the activation of tumor-specific cytotoxic T cells, their recruitment into the tumor site, and tumor regression. Finally, the concurrent administration of granulocyte colony-stimulating factor (G-CSF) enhanced RT-mediated antitumor activity by activating RT-Ns. Our results suggest that the combination of RT and G-CSF should be further evaluated in preclinical and clinical settings.
AB - Radiation therapy (RT), a major modality for treating localized tumors, can induce tumor regression outside the radiation field through an abscopal effect that is thought to involve the immune system. Our studies were designed to understand the early immunological effects of RT in the tumor microenvironment using several syngeneic mouse tumor models. We observed that RT induced sterile inflammation with a rapid and transient infiltration of CD11b+Gr-1high+ neutrophils into the tumors. RT-recruited tumor-associated neutrophils (RT-Ns) exhibited an increased production of reactive oxygen species and induced apoptosis of tumor cells. Tumor infiltration of RT-Ns resulted in sterile inflammation and, eventually, the activation of tumor-specific cytotoxic T cells, their recruitment into the tumor site, and tumor regression. Finally, the concurrent administration of granulocyte colony-stimulating factor (G-CSF) enhanced RT-mediated antitumor activity by activating RT-Ns. Our results suggest that the combination of RT and G-CSF should be further evaluated in preclinical and clinical settings.
KW - G-CSF
KW - Radiation therapy
KW - Tumor-associated neutrophils
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U2 - 10.1073/pnas.1613187113
DO - 10.1073/pnas.1613187113
M3 - Article
C2 - 27651484
AN - SCOPUS:84989948632
SN - 0027-8424
VL - 113
SP - 11300
EP - 11305
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
ER -