6,633 research outputs found
A systems genetics approach to the characterization of differential low dose radiation responses in BXD recombinant inbred mice
High doses of radiation (HDR) are clearly detrimental to human health, but relatively little is known about the health consequences following exposure to low doses of radiation (LDR, \u3c10cGy). Understanding the risks associated with LDR is of great importance to the general public due to the recent dramatic increase in diagnostic radiological imaging. While HDR clearly suppress immune function, there is evidence that LDR can be immunostimulatory. Within the organism, defining the consequences of LDR is further complicated by the impact of genetic background, particularly in systems such as the immune system for which both radiosensitivity and genetic effects are profound.
We addressed the issue of genetic susceptibility to LDR using the immune system as a target system and treated the LDR response as a complex trait analyzed using a systems genetics framework. Using the BXD recombinant inbred strain mouse panel as a genetic reference population allowed us to address the radiation response within the context of natural genetic variation. Our overarching hypothesis is that, within a population, the immunological effects of LDR exposure depend in part on the individual’s baseline immunoprofile and gene expression which are ultimately dependent upon genetic background. We began by establishing the immunophenotypic variation (i.e., T:B cell ratio, CD4:CD8 ratio) within the BXD panel and used baseline spleen transcriptome profiling to identify putative candidate genes controlling these traits, specifically Acp1 and Ptprk for CD4:CD8 ratio. The same set of BXD strains was exposed to LDR (10cGy gamma radiation) to determine effects on immune function and oxidative stress. LDR significantly enhanced neutrophil phagocytosis in a manner that was independent of genetic background. In contrast, genetic background significantly impacted LDR-induced changes in spleen superoxide dismutase activity.
By integrating these results with our previous analyses of BXD RI strains, we have demonstrated that baseline expression of Sod2 correlates with LDR-induced SOD activity, and baseline CD4:CD8 ratio is inversely correlated with LDR-induced neutrophil phagocytosis. In addition, spleen transcriptomic data from the BXD parental strains further highlighted the impact of genetic background on LDR responses. These data provide the groundwork for predicting LDR responses using baseline expression, immunophenotypes, and/or genotype
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Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.
PurposeGlioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies.Methods and materialsA number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration.ResultsVarious immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials.ConclusionsThis review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response
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Immune targets in the tumor microenvironment treated by radiotherapy.
Radiotherapy (RT), the major anti-cancer modality for more than half of cancer patients after diagnosis, has the advantage of local tumor control with relatively less systematic side effects comparing to chemotherapy. However, the efficacy of RT is limited by acquired tumor resistance leading to the risks of relapse and metastasis. To further enhance the efficacy of RT, with the renaissances of targeted immunotherapy (TIT), increasing interests are raised on RT combined with TIT including cancer vaccines, T-cell therapy, and antibody-based immune checkpoint blockers (ICB) such as anti-CTLA-4 and anti-PD1/PD-L1. In achieving a significant synergy between RT and TIT, the dynamics of radiation-induced response in tumor cells and stromal cells, especially the cross-talk between tumor cells and immune cells in the irradiated tumor microenvironment (ITME) as highlighted in recent literature are to be elucidated. The abscopal effect refereeing the RT-induced priming function outside of ITME could be compromised by the immune-suppressive factors such as CD47 and PD-L1 on tumor cells and Treg induced or enhanced in the ITME. Cell surface receptors temporally or permanently induced and bioactive elements released from dead cells could serve antigenic source (radiation-associated antigenic proteins, RAAPs) to the host and have functions in immune regulation on the tumor. This review is attempted to summarize a cluster of factors that are inducible by radiation and targetable by antibodies, or have potential to be immune regulators to synergize tumor control with RT. Further characterization of immune regulators in ITME will deepen our understanding of the interplay among immune regulators in ITME and discover new effective targets for the combined modality with RT and TIT
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EXTH-08. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION
Abstract
Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits
Gene expression profiles among murine strains segregate with distinct differences in the progression of radiation-induced lung disease.
Molecular mechanisms underlying development of acute pneumonitis and/or late fibrosis following thoracic irradiation remain poorly understood. Here, we hypothesize that heterogeneity in disease progression and phenotypic expression of radiation-induced lung disease (RILD) across murine strains presents an opportunity to better elucidate mechanisms driving tissue response toward pneumonitis and/or fibrosis. Distinct differences in disease progression were observed in age- and sex-matched CBA/J, C57L/J and C57BL/6J mice over 1 year after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 h post-exposure demonstrated \u3e5000 genes to be differentially expressed (P\u3c0.01; \u3etwofold change) between strains with early versus late onset of disease. An immediate divergence in early tissue response between radiation-sensitive and -resistant strains was observed. In pneumonitis-prone C57L/J mice, differentially expressed genes were enriched in proinflammatory pathways, whereas in fibrosis-prone C57BL/6J mice, genes were enriched in pathways involved in purine and pyrimidine synthesis, DNA replication and cell division. At 24 h post-WTLI, different patterns of cellular damage were observed at the ultrastructural level among strains but microscopic damage was not yet evident under light microscopy. These data point toward a fundamental difference in patterns of early pulmonary tissue response to WTLI, consistent with the macroscopic expression of injury manifesting weeks to months after exposure. Understanding the mechanisms underlying development of RILD might lead to more rational selection of therapeutic interventions to mitigate healthy tissue damage
Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models
Purpose: Glioblastoma multiforme (GBM) is the most aggressive brain tumor. The activity of vosaroxin, a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, was investigated in GBM preclinical models as a single agent and combined with radiotherapy (RT). Results: Vosaroxin showed antitumor activity in clonogenic survival assays, with IC50 of 10-100 nM, and demonstrated radiosensitization. Combined treatments exhibited significantly higher ÎłH2Ax levels compared with controls. In xenograft models, vosaroxin reduced tumor growth and showed enhanced activity with RT; vosaroxin/RT combined was more effective than temozolomide/RT. Vosaroxin/ RT triggered rapid and massive cell death with characteristics of necrosis. A minor proportion of treated cells underwent caspase-dependent apoptosis, in agreement with in vitro results. Vosaroxin/RT inhibited RT-induced autophagy, increasing necrosis. This was associated with increased recruitment of granulocytes, monocytes, and undifferentiated bone marrow-derived lymphoid cells. Pharmacokinetic analyses revealed adequate blood-brain penetration of vosaroxin. Vosaroxin/RT increased disease-free survival (DFS) and overall survival (OS) significantly compared with RT, vosaroxin alone, temozolomide, and temozolomide/RT in the U251-luciferase orthotopic model. Materials and Methods: Cellular, molecular, and antiproliferative effects of vosaroxin alone or combined with RT were evaluated in 13 GBM cell lines. Tumor growth delay was determined in U87MG, U251, and T98G xenograft mouse models. (DFS) and (OS) were assessed in orthotopic intrabrain models using luciferasetransfected U251 cells by bioluminescence and magnetic resonance imaging. Conclusions: Vosaroxin demonstrated significant activity in vitro and in vivo in GBM models, and showed additive/synergistic activity when combined with RT in O6- methylguanine methyltransferase-negative and -positive cell lines
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Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC
Improving treatment of glioblastoma: new insights in targeting cancer stem cells effectively
Glioblastoma is the most common primary malignant brain tumour in the adult population.
Despite multimodality treatment with surgery, radiotherapy and chemotherapy, outcomes are
very poor, with less than 15% of patients alive after two years. Increasing evidence suggests
that glioblastoma stem cells (GSCs) are likely to play an important role in the biology of this
disease and are involved in treatment resistance and tumour recurrence following standard
therapy.
My thesis aims to address two main aspects of this research area: 1) optimization of methods
to evaluate treatment responses of GSCs and their differentiated counterparts (non-GSCs),
with a particular focus on a tissue culture model that resembles more closely the tumoral
niche; 2) characterization of cell division and centrosome cycle of GSCs, investigating possible
differences between these cells and non-GSCs, that would allow the identification of targets
for new therapeutic strategies against glioblastomas.
In the first part of my project, I optimized a clonogenic survival assay, to compare sensitivity of
GSCs and non-GSCs to various treatments, and I developed the use of a 3-dimentional tissue
culture system, that allows analysis of features and radiation responses of these two
subpopulations in the presence of specific microenvironmental factors from the tumoral niche.
In the second part, I show that GSCs display mitotic spindle abnormalities more frequently
than non-GSCs and that they have distinctive features with regards to the centrosome cycle. I
also demonstrate that GSCs are more sensitive than non-GSCs to subtle changes in Aurora
kinase A activity, which result in a rapid increase in polyploidy and subsequently in senescence,
with a consistent reduction in clonogenic survival. Based on these findings, I propose that
kinases involved in the centrosome cycle need to be explored as a novel strategy to target
GSCs effectively and improve outcomes of glioblastoma patients
Dynamic regulation of CD4+ regulatory T cells by radiation treatment
Radiotherapy remains effective at treating primary, early-stage tumors, however it produces nominal results in late-stage and metastatic tumors. This has led to a shift towards more targeted immune-based therapies. Yet the use of most approved cancer immunotherapies is limited to only a few cancer types and in the absence of effective anti-tumor immunity tumors can successfully evade immune surveillance. Tumors employ multiple mechanisms for avoiding immune elimination including down-regulation of positive signals to tumor specific CD8+ cytotoxic T cells (CTLs) and the accumulation of CD4+ regulatory T (TREG) cells which can suppress the anti-tumor activity of effector CTLs. Radiation has been reported to enhance anti-tumor immunity through such mechanisms as tumor cell death or phenotypic modulation of tumor cells, however the impact of radiotherapy on TREGcells is less clear.
The goal of this dissertation was to investigate the direct effect of radiation on the phenotypic characteristics and functional activity of induced TREGcells and to examine the indirect effect of radiation on TREGfrequency. We found that exposure to sub-lethal radiation decreased the expression of Foxp3 in TREGcells and differentially modulated the expression of several TREGsignature molecules. This loss of Foxp3 and modulation of several TREGassociated molecules resulted in a reduction of suppressive activity. Radiation has previously been shown to modulate the expression of genes in tumor cells that can impact T cell activity such as OX40L and 4-1BBL. Thus, a secondary goal of the research was to assess the effect of radiation-induced expression of tumoral OX40L and 4-1BBL on TREGnumber in two commonly used tumor models, 4T1 and MC38. Additionally, we examined 4T1 and MC38 tumors for changes in immune cell composition post-treatment. We found that radiation differentially modulated OX40L and 4-1BBL expression in our tumor models, as well as reduced TREGfrequency. However, induced expression of OX40L did not correlate with the observed decrease in TREGfrequency. Further, we found that radiotherapy differentially modulated the immune cell profile of 4T1 and MC38 tumors. These findings could support the design for rationale combinations of cancer immunotherapies with radiation treatment
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