Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric i... more Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleas...
Purpose of Review Glioblastoma is the commonest primary brain cancer in adults whose outcomes are... more Purpose of Review Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically. Recent Findings Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and severa...
Quantitative differences in signal transduction are to date an understudied feature of tumour het... more Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to metastatic tumours, despite the evolutionary trade-off of increased apoptotic death in the liver that c...
We thank Alisi and colleagues for their comments [1] on our recent report characterizing the effe... more We thank Alisi and colleagues for their comments [1] on our recent report characterizing the effects of the hepatitis C virus (HCV) proteins on metabolic liver zonation and steatosis [2]. In a transgenic mouse model with hepato-specific expression of the full complement of HCV proteins we found that fatty acid synthase, a major lipogenic enzyme, was redistributed to the midzone of the lobule, coinciding with zonated accumulation of lipids. Based on these and additional results, we hypothesized that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. However, not all genes that display zonated expression in the liver were altered in the animal model studied. Notably, we found no change in the pattern of expression of E-cadherin or arginase 1. In contrast to the results reported by Alisi et al. we did not study the global level of expression of the latter. Alisi et al. compared arginase 1 expression in liver tissues from children with no hepatic pathologies or suffering from non-alcoholic fatty liver disease (NAFLD) or hepatitis C [1]. The quantification of the immunhistochemical staining showed identical mean intensity of arginase 1 in healthy livers and in HCVpositive patients without steatosis. This is consistent with our results showing no difference of arginase 1 expression in hepatocytes from control and HCV-transgenic mice [2]. In our work, appearance of steatosis did not alter arginase distribution. In contrast, Alisi et al. observed increased arginase 1 expression in HCV patients with steatosis and in NAFLD. Their results highlight the link between lipid accumulation and arginase expression, as well as the effect of HCV infection on arginase 1 accumulation. Noteworthy, Alisi et al. give no information on the HCV genotype, while our study focused solely on genotype 1. It would be of interest to determine whether the reported observations are genotype specific or more generalizable. As Alisi and colleagues correctly pointed out, the role of arginase 1 in steatosis is not well understood and possibly underestimated. Interestingly, its increased expression has been described in HCV infection and it was suggested that it might participate in promoting cell growth and proliferation [3]. Indeed, arginase 1 converts arginine to ornithine, which is further metabolized to polyamines that promote cellular proliferation. Thus, elevated arginase 1 expression may be hepatoprotective during chronic infection by promoting survival and proliferation of HCV-infected hepatocytes. In consequence, the inflammatory immune response that contributes to liver damage would be inefficient in eliminating virus-infected cells. Elevated arginase 1 expression is associated with many tumor types [4] and therapeutic strategies aiming at inhibiting this metabolic pathway are being tested in the clinic. Interestingly, in HCC, the predominant peri-tumoral distribution of arginase 1 expression is in agreement with proteomic analyses of samples from HCV infected HCC and non-tumoral liver [3,5]. Recent evidence indicates that interactions between tumor cells and the host microenvironment have a major role in driving cancer progression and metastasis [6,7]. The abundance of macrophages, pivotal members of tumor stroma, strongly correlates with poor prognosis in different types of solid tumors, including HCC [8]. It has been proposed that tumor-associated macrophages (M2-polarized) play an important role in generating overall immunosuppressive milieu within the tumor microenvironment that suppresses anti-tumor immunity and promotes tumor progression [6]. Interestingly, the differential metabolism of L-arginine provides a means of distinguishing the two macrophage activation states. M1, or classically activated macrophages, upregulate iNOS to catabolize L-arginine to nitric oxide and citrulline, while M2, or alternatively activated macrophages, induce arginase 1, the enzyme upstream of polyamines production, and thus increase collagen synthesis and cellular proliferation [9]. In HCC, high numbers of peri-tumoral M2-polarized TAMs are associated with poor patient prognosis, and while no analyses of arginase 1 expression have yet been conducted in this context, it is likely that they express high levels of this enzyme along with the other M2 genes described. In this context, TAM-derived arginase 1 might promote tumorigenesis in a non-cell autonomous manner. Furthermore, several TAM-derived factors, such as
Hepatocellular carcinoma (HCC), a malignancy that arises in the context of a damaged liver, is th... more Hepatocellular carcinoma (HCC), a malignancy that arises in the context of a damaged liver, is the second leading cause of cancer-related mortality worldwide, in part due to limited effective treatment and the rapid development of resistance. While many studies have focused on the cellular changes that drive resistance to therapy, little attention has been given to the role that liver tumor microenvironment plays in this process. Liver fibrosis, extracellular matrix accumulation, angiogenesis, hypoxia, and inflammation are factors that directly contribute to liver tumorigenesis and can also promote resistance. Understanding the interactions of the components of the liver tumor microenvironment with cancer cells will be critical to design strategies to overcome resistance and improve the therapeutic efficacy of current and future therapies.
Leila Akkari began her independent career in 2017 as an Assistant Professor at the Netherlands Ca... more Leila Akkari began her independent career in 2017 as an Assistant Professor at the Netherlands Cancer Institute in Amsterdam after working at Memorial Sloan Kettering Cancer Center in NYC. Two years ago, she was selected as one of the junior members of the Oncode Institute, a virtual group of cancer research labs based on the Netherlands. In this short Q&A, she tells us about her research and how her diverse background has helped her as a scientist. Dr. Akkari also shares some great pointers on the biggest hurdles women in STEM face and tips to overcome them.
Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma developmen... more Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor–1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has...
Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric i... more Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleas...
Purpose of Review Glioblastoma is the commonest primary brain cancer in adults whose outcomes are... more Purpose of Review Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically. Recent Findings Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and severa...
Quantitative differences in signal transduction are to date an understudied feature of tumour het... more Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to metastatic tumours, despite the evolutionary trade-off of increased apoptotic death in the liver that c...
We thank Alisi and colleagues for their comments [1] on our recent report characterizing the effe... more We thank Alisi and colleagues for their comments [1] on our recent report characterizing the effects of the hepatitis C virus (HCV) proteins on metabolic liver zonation and steatosis [2]. In a transgenic mouse model with hepato-specific expression of the full complement of HCV proteins we found that fatty acid synthase, a major lipogenic enzyme, was redistributed to the midzone of the lobule, coinciding with zonated accumulation of lipids. Based on these and additional results, we hypothesized that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. However, not all genes that display zonated expression in the liver were altered in the animal model studied. Notably, we found no change in the pattern of expression of E-cadherin or arginase 1. In contrast to the results reported by Alisi et al. we did not study the global level of expression of the latter. Alisi et al. compared arginase 1 expression in liver tissues from children with no hepatic pathologies or suffering from non-alcoholic fatty liver disease (NAFLD) or hepatitis C [1]. The quantification of the immunhistochemical staining showed identical mean intensity of arginase 1 in healthy livers and in HCVpositive patients without steatosis. This is consistent with our results showing no difference of arginase 1 expression in hepatocytes from control and HCV-transgenic mice [2]. In our work, appearance of steatosis did not alter arginase distribution. In contrast, Alisi et al. observed increased arginase 1 expression in HCV patients with steatosis and in NAFLD. Their results highlight the link between lipid accumulation and arginase expression, as well as the effect of HCV infection on arginase 1 accumulation. Noteworthy, Alisi et al. give no information on the HCV genotype, while our study focused solely on genotype 1. It would be of interest to determine whether the reported observations are genotype specific or more generalizable. As Alisi and colleagues correctly pointed out, the role of arginase 1 in steatosis is not well understood and possibly underestimated. Interestingly, its increased expression has been described in HCV infection and it was suggested that it might participate in promoting cell growth and proliferation [3]. Indeed, arginase 1 converts arginine to ornithine, which is further metabolized to polyamines that promote cellular proliferation. Thus, elevated arginase 1 expression may be hepatoprotective during chronic infection by promoting survival and proliferation of HCV-infected hepatocytes. In consequence, the inflammatory immune response that contributes to liver damage would be inefficient in eliminating virus-infected cells. Elevated arginase 1 expression is associated with many tumor types [4] and therapeutic strategies aiming at inhibiting this metabolic pathway are being tested in the clinic. Interestingly, in HCC, the predominant peri-tumoral distribution of arginase 1 expression is in agreement with proteomic analyses of samples from HCV infected HCC and non-tumoral liver [3,5]. Recent evidence indicates that interactions between tumor cells and the host microenvironment have a major role in driving cancer progression and metastasis [6,7]. The abundance of macrophages, pivotal members of tumor stroma, strongly correlates with poor prognosis in different types of solid tumors, including HCC [8]. It has been proposed that tumor-associated macrophages (M2-polarized) play an important role in generating overall immunosuppressive milieu within the tumor microenvironment that suppresses anti-tumor immunity and promotes tumor progression [6]. Interestingly, the differential metabolism of L-arginine provides a means of distinguishing the two macrophage activation states. M1, or classically activated macrophages, upregulate iNOS to catabolize L-arginine to nitric oxide and citrulline, while M2, or alternatively activated macrophages, induce arginase 1, the enzyme upstream of polyamines production, and thus increase collagen synthesis and cellular proliferation [9]. In HCC, high numbers of peri-tumoral M2-polarized TAMs are associated with poor patient prognosis, and while no analyses of arginase 1 expression have yet been conducted in this context, it is likely that they express high levels of this enzyme along with the other M2 genes described. In this context, TAM-derived arginase 1 might promote tumorigenesis in a non-cell autonomous manner. Furthermore, several TAM-derived factors, such as
Hepatocellular carcinoma (HCC), a malignancy that arises in the context of a damaged liver, is th... more Hepatocellular carcinoma (HCC), a malignancy that arises in the context of a damaged liver, is the second leading cause of cancer-related mortality worldwide, in part due to limited effective treatment and the rapid development of resistance. While many studies have focused on the cellular changes that drive resistance to therapy, little attention has been given to the role that liver tumor microenvironment plays in this process. Liver fibrosis, extracellular matrix accumulation, angiogenesis, hypoxia, and inflammation are factors that directly contribute to liver tumorigenesis and can also promote resistance. Understanding the interactions of the components of the liver tumor microenvironment with cancer cells will be critical to design strategies to overcome resistance and improve the therapeutic efficacy of current and future therapies.
Leila Akkari began her independent career in 2017 as an Assistant Professor at the Netherlands Ca... more Leila Akkari began her independent career in 2017 as an Assistant Professor at the Netherlands Cancer Institute in Amsterdam after working at Memorial Sloan Kettering Cancer Center in NYC. Two years ago, she was selected as one of the junior members of the Oncode Institute, a virtual group of cancer research labs based on the Netherlands. In this short Q&A, she tells us about her research and how her diverse background has helped her as a scientist. Dr. Akkari also shares some great pointers on the biggest hurdles women in STEM face and tips to overcome them.
Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma developmen... more Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor–1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has...
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