biostudies-literatureChae MNCI NIH HHS978-91https://www.ebi.ac.uk/biostudies/studies/S-EPMC5654350biostudies-literatureUnknown17(7)<h4>Background</h4>Patients with glioblastoma multiforme (GBM) exhibit marked intratumoral and systemic immunosuppression. GBM is heavily infiltrated with monocytic cells. Monocytes contacting GBM cells develop features of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are elevated in GBM patients. Therefore, we hypothesized that circulating MDSC levels could be raised in vivo by increasing glioma-associated macrophages.<h4>Methods</h4>GL261-luciferase glioma was implanted intracranially in C57BL/6 mice with or without additional normal syngeneic CD11b+ monocytes. Tumor growth and intratumoral and systemic MDSC (CD11b+/Gr-1+) levels were determined. Green fluorescent protein (GFP)-transgenic monocytes were coinjected intracranially with GL261-luciferase cells. GFP+ cell frequency among splenic and bone marrow MDSCs was determined. Impact of increased MDSC's on spontaneous immune responses to tumor cells expressing a model antigen (ovalbumin [OVA]) was determined.<h4>Results</h4>Tumors grew faster and MDSC's were increased in tumor, spleen, and bone marrow in mice receiving GL261-Luc plus monocytes. Many (30%-50%) systemic MDSC's were GFP+ in mice receiving intracranial tumor plus GFP-transgenic monocytes, suggesting that they originated from glioma-associated monocytes. Tumor-infiltrating OVA-specific CD8+ T cells were markedly reduced in mice receiving GL261-OVA and monocytes compared with mice receiving GL261-OVA alone.<h4>Conclusions</h4>Increasing glioma-associated macrophages in intracranial GL261 glioma decreases survival and markedly increases intratumoral and systemic MDSC's, many of which originate directly from glioma-associated macrophages. This is associated with decreased spontaneous immune responses to a model antigen. To our knowledge, this is the first evidence in cancer that systemic MDSC's can arise directly from normal monocytes that have undergone intratumoral immunosuppressive education.Neuro-oncologyIncreasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model.PMC56543501P50CA108961-06P50 CA108961R21 CA186976Renner DNBalgeman APeterson TEJohnson AJParney IFZhang LChen SChae MfalseIncreasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model.<h4>Background</h4>Patients with glioblastoma multiforme (GBM) exhibit marked intratumoral and systemic immunosuppression. GBM is heavily infiltrated with monocytic cells. Monocytes contacting GBM cells develop features of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are elevated in GBM patients. Therefore, we hypothesized that circulating MDSC levels could be raised in vivo by increasing glioma-associated macrophages.<h4>Methods</h4>GL261-luciferase glioma was implanted intracranially in C57BL/6 mice with or without additional normal syngeneic CD11b+ monocytes. Tumor growth and intratumoral and systemic MDSC (CD11b+/Gr-1+) levels were determined. Green fluorescent protein (GFP)-transgenic monocytes were coinjected intracranially with GL261-luciferase cells. GFP+ cell frequency among splenic and bone marrow MDSCs was determined. Impact of increased MDSC's on spontaneous immune responses to tumor cells expressing a model antigen (ovalbumin [OVA]) was determined.<h4>Results</h4>Tumors grew faster and MDSC's were increased in tumor, spleen, and bone marrow in mice receiving GL261-Luc plus monocytes. Many (30%-50%) systemic MDSC's were GFP+ in mice receiving intracranial tumor plus GFP-transgenic monocytes, suggesting that they originated from glioma-associated monocytes. Tumor-infiltrating OVA-specific CD8+ T cells were markedly reduced in mice receiving GL261-OVA and monocytes compared with mice receiving GL261-OVA alone.<h4>Conclusions</h4>Increasing glioma-associated macrophages in intracranial GL261 glioma decreases survival and markedly increases intratumoral and systemic MDSC's, many of which originate directly from glioma-associated macrophages. This is associated with decreased spontaneous immune responses to a model antigen. To our knowledge, this is the first evidence in cancer that systemic MDSC's can arise directly from normal monocytes that have undergone intratumoral immunosuppressive education.2015-01-01T00:00:00Z2015 Jul2024-10-16T08:26:30.069Z2019-03-27T02:59:46ZS-EPMC56543502553701910.1093/neuonc/nou343