在小鼠模型中，增加胶质瘤相关单核细胞会导致肿瘤内和全身骨髓来源的抑制细胞增多。
Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model.
作者信息
Chae Michael, Peterson Timothy E, Balgeman Alexis, Chen Selby, Zhang Lei, Renner Danielle N, Johnson Aaron J, Parney Ian F
机构信息
Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
出版信息
Neuro Oncol. 2015 Jul;17(7):978-91. doi: 10.1093/neuonc/nou343. Epub 2014 Dec 23.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
背景
多形性胶质母细胞瘤（GBM）患者表现出明显的肿瘤内和全身免疫抑制。GBM中有大量单核细胞浸润。与GBM细胞接触的单核细胞会发展出免疫抑制性髓系来源抑制细胞（MDSC）的特征，GBM患者体内这种细胞水平升高。因此，我们推测通过增加胶质瘤相关巨噬细胞可在体内提高循环MDSC水平。
方法
将GL261 - 荧光素酶胶质瘤颅内植入C57BL / 6小鼠，分别植入或不植入额外的同基因正常CD11b +单核细胞。测定肿瘤生长以及肿瘤内和全身MDSC（CD11b + / Gr - 1 +）水平。将绿色荧光蛋白（GFP）转基因单核细胞与GL261 - 荧光素酶细胞一起颅内注射。测定脾脏和骨髓MDSC中GFP +细胞频率。确定增加的MDSC对表达模型抗原（卵清蛋白[OVA]）的肿瘤细胞的自发免疫反应的影响。
结果
接受GL261 - Luc加单核细胞的小鼠肿瘤生长更快，肿瘤、脾脏和骨髓中的MDSC增加。在接受颅内肿瘤加GFP转基因单核细胞的小鼠中，许多（30% - 50%）全身MDSC为GFP +，表明它们起源于胶质瘤相关单核细胞。与仅接受GL261 - OVA的小鼠相比，接受GL261 - OVA和单核细胞的小鼠中肿瘤浸润的OVA特异性CD8 + T细胞明显减少。
结论
颅内GL261胶质瘤中增加胶质瘤相关巨噬细胞会降低生存率，并显著增加肿瘤内和全身MDSC，其中许多直接起源于胶质瘤相关巨噬细胞。这与对模型抗原的自发免疫反应降低有关。据我们所知，这是癌症中首个证据表明全身MDSC可直接源自经历肿瘤内免疫抑制诱导的正常单核细胞。
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