Here we report that glioblastoma multiforme (GBM) mediates immunosuppression by promoting T-cell death via tumorassociated CD70 and gangliosides that act through receptordependent and receptor-independent pathways, respectively. GBM lines cocultured with T cells induced lymphocyte death. The GBM lines were characterized for their expression of CD70, Fas ligand (FasL), and tumor necrosis factor-A (TNF-A), and the possible participation of those molecules in T-cell killing was assessed by doing GBM/T cell cocultures in the presence of anti-CD70 antibodies, Fas fusion proteins, or anti-TNF-A antibodies. CD70 but not TNF-A or FasL is responsible for initiating T-cell death via the receptor-dependent pathway. Of the four GBM cell lines that induced T-cell death, three highly expressed CD70. Two nonapoptogenic GBM lines (CCF3 and U138), on the other hand, had only minimally detectable CD70 expression. Blocking experiments with the anti-CD70 antibody confirmed that elevated CD70 levels were involved in the apoptogenicity of the three GBM lines expressing that molecule. Gangliosides were found to participate in the induction of T-cell apoptosis, because the glucosylceramide synthase inhibitor (PPPP) significantly reduced the abilities of all four apoptogenic lines to kill the lymphocytes. Highperformance liquid chromatography (HPLC) and mass spectroscopy revealed that GM2, GM2-like gangliosides, and GD1a were synthesized in abundance by all four apoptogenic GBM lines but not by the two GBMs lacking activity. Furthermore, gangliosides isolated from GBM lines as well as HPLC fractions containing GM2 and GD1a were directly apoptogenic for T cells. Our results indicate that CD70 and gangliosides are both products synthesized by GBMs that may be key mediators of T-cell apoptosis and likely contribute to the T-cell dysfunction observed within the tumor microenvironment. (Cancer Res 2005; 65(12): 5428-38)
Some tumor cell lines secrete high concentrations of TGF or IL-1. Similarly high concentrations of each of these cytokines cross-activate the other pathway: TGF activates NFB, and IL-1 activates Smads. The IL-1 signaling components IRAK, MyD88, TRAF6, and TAK1 are all required for cross-activation of NFB by TGF. Knockdown experiments revealed that both TGF receptor subunits are required for IL-1 to activate Smads, and the IL-1 receptor is required for TGF to activate NFB. Coimmunoprecipitations showed that either TGF or IL-1 stimulate ligand-dependent association of all three receptor subunits. Furthermore, cross-talk between the TGF and IL-1 signaling pathways leads to dose-dependent cross-control of gene expression. These interactions provide new insight into biological responses to IL-1 and TGF in the proximity of tumors that secrete high concentrations of these factors and probably also at sites of inflammation, where the local concentrations of these cytokines are likely to be high.cytokine receptors ͉ NFB ͉ Smad ͉ TLRs M embers of the TGF superfamily regulate many developmental processes, and TGF is involved in many human diseases, including cancer, where it functions, paradoxically, both as an antiproliferative factor and a tumor promoter (1). The TGF receptor (TR) is a complex of two single-pass transmembrane subunits, TRI and TRII, which contain intracellular serine/ threonine kinase domains. Ligand binding induces TRI and TRII to associate, leading to the phosphorylation of TRI by TRII, activating its kinase domain. Activated TRI then phosphorylates and activates the transcription factors Smad 2 and Smad 3 (1, 2). TGF can also activate other signaling proteins, including MAP kinases and, especially relevant to the work reported here, NFB (3, 4). The balance between Smad activation and other signals is likely to help determine whether TGF suppresses or promotes cancer (1, 2).IL-1 plays a crucial role in inflammation, stress, and disease (5, 6). IL-1␣ or IL-1 bind to and activate the IL-1 receptor (IL-1R) (5). IL-1R and the adaptor protein myeloid differentiation factor 88 (MyD88) interact through their intracellular domains (5-7). The death domain of MyD88 then recruits the IL-1R-associated kinase (IRAK) to the receptor complex (5, 7). IRAK is phosphorylated, dissociates from the receptor complex, and recruits tumor necrosis factor ␣ receptor-associated factor 6 (TRAF6), which in turn activates the downstream kinase TGF activating kinase 1 (TAK1), eventually leading to the activation of inhibitor of NFB (IB), the phosphorylation and degradation of IB, and the activation of NFB (5-8). Responses to IL-1 are amplified through an autocrine loop. For example, astrocytoma cells respond to treatment with IL-1 by up-regulating mRNAs encoding IL-1␣ or IL-1, IL-1R, and tumor necrosis factor ␣ mRNAs (9). Recent work reveals that this autocrine loop plays an important role in the development of resistance to the antitumor drug camptothecin, which induces the expression of IL-1 by activa...
Despite major therapeutic advances in the management of patients with systemic malignancies, management of brain metastases remains a significant challenge. These patients often require multidisciplinary care that includes surgical resection, radiation therapy, chemotherapy, and targeted therapies. Complex decisions about the sequencing of therapies to control extracranial and intracranial disease require input from neurosurgeons, radiation oncologists, and medical/neuro-oncologists. With advances in understanding of the biology of brain metastases, molecularly defined disease subsets and the advent of targeted therapy as well as immunotherapeutic agents offer promise. Future care of these patients will entail tailoring treatment based on host (performance status and age) and tumor (molecular cytogenetic characteristics, number of metastases, and extracranial disease status) factors. Considerable work involving preclinical models and better clinical trial designs that focus not only on effective control of tumor but also on quality of life and neurocognition needs to be done to improve the outcome of these patients.
Time to progression (TTP) is an established response measure, and at progression patients can be included in trials. Standards for imaging interpretation of progression are lacking. We determined the differences in time to progression and in tumor volumes at progression between three methods to assess progression. METHODS: From a consecutive cohort of 97 patients with glioblastoma in 2012 or 2013, 63 had MRI follow-up after initial treatment to evaluate progression. TTPclinical was determined by multidisciplinary evaluation in clinical practice; TTPRANO by the RANO criteria for trial inclusion; and TTPconsensus by multidisciplinary consensus review (neuroradiologist, neurosurgeon, 2 radiation oncologists) looking back on all MRI information (on average 3.9 follow-up MRIs per patient, range 1-11) with knowledge of further progression and death, postulated as gold standard. MRIs were co-registered to facilitate the consensus review and the maximum perpendicular tumor diameters and volumes were based on enhancing tumor segmentations. RESULTS: No patient was without progression with consensus review, one with clinical practice evaluation and 22 with RANO criteria. The median TTPconsensus was 36 weeks, TTPclinical 40 weeks and TTPRANO 57 weeks. The median overall survival was 64 weeks. The median progression volume was 8.8 mL with consensus review, 17 mL with clinical practice evaluation, and 38 mL with RANO. CONCLUSION: TTP and volume at progression vary considerably depending on definition of progression. Different purposes may require different progression criteria. Early detection with small volumes may be useful to evaluate progression locations in relation to initial treatment, but can only be determined after the course of disease. RANO criteria may be useful for reproducible clinical trial inclusion, but at the price of later detection with larger volumes. Progression according to RANO criteria is considerably later than clinical practice evaluation in this cohort, potentially introducing lead time bias in trials. HOUT-15.
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