TY - JOUR
T1 - Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model
AU - McGinnis, Gwendolyn J.
AU - Friedman, David
AU - Young, Kristina H.
AU - Torres, Eileen Ruth S.
AU - Thomas, Charles R.
AU - Gough, Michael J.
AU - Raber, Jacob
N1 - Funding Information:
The authors would like to thank Blair Stewart, Tessa Marzulla, Sydney Weber, Lance Johnson, Tunde Akinyeke, Damien Zuloaga, Amelia Mulford, Gwen Kramer and Shelly Bambina for their invaluable assistance. G.J.M. was supported by an HHMI Medical Research Fellowship, the Collins Medical Trust, an RSNA Research Medical Student Grant (RMS1416), an N.L. Tartar Research Fellowship, the Oregon Clinical and Translational Research Institute (OCTRI) grant number UL1 RR024140 from the National Center for Research Resources (NCRR), the William Moss Kenneth Stevens Academic Development Fund of the Department of Radiation Medicine, and the development account of J.R. The tumor models and radiation treatment were supported by NCI R01 CA182311 and an instrument grant from the MJ Murdock Charitable Trust and the Providence Research Foundation. K.H.Y. was a recipient of an RSNA R&E Foundation Research Resident Grant.
PY - 2017
Y1 - 2017
N2 - Background: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. Results: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). Materials and Methods: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. Conclusions: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation.
AB - Background: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. Results: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). Materials and Methods: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. Conclusions: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation.
KW - Cancer-related neurological dysfunction
KW - Immunotherapy
KW - Microglia
KW - Neuroinflammation
KW - Radiotherapy
UR - http://www.scopus.com/inward/record.url?scp=85011961559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011961559&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13551
DO - 10.18632/oncotarget.13551
M3 - Article
C2 - 27893434
AN - SCOPUS:85011961559
SN - 1949-2553
VL - 8
SP - 9155
EP - 9173
JO - Oncotarget
JF - Oncotarget
IS - 6
ER -