Tumour ischaemia by interferon-γ resembles physiological blood vessel regression

Kammertoens, Thomas; Friese, Christian; Arina, Ainhoa; Idel, Christian; Briesemeister, Dana; Rothe, Michael; Ivanov, Andranik; Szymborska, Anna; Patone, Giannino; Kunz, Séverine; Sommermeyer, Daniel; Engels, Boris; Leisegang, Matthias; Textor, Ana; Fehling, Hans Jöerg; Fruttiger, Marcus; Lohoff, Michael; Herrmann, Andreas; Yu, Hua; Weichselbaum, Ralph R.; Uckert, Wolfgang; Hübner, Norbert; Gerhardt, Holger; Beule, Dieter; Schreiber, Hans; Blankenstein, Thomas

doi:10.1038/nature22311

Cited by 197 publications

(164 citation statements)

References 38 publications

(42 reference statements)

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“…Moreover, IFNγ is a major mediator of antitumor immunity with robust antiangiogenic activity 3,83,84,93 . A recent study induced IFNγ expression in murine fibrosarcoma and adenocarcinoma cells and selectively expressed IFNγ receptor in specific stromal cell types, including myeloid cells, fibroblasts, T cells, and endothelial cells; this study found that IFNγ directly promoted tumour vessel regression and blood flow arrest via its interactions with tumour endothelial cell IFNγ receptors, leading to intratumoral ischemia and subsequent collapse of the tumour 92 . The apparent discrepancy between this finding and the recent evidence that IFNγ promoted vessel normalization 75 could be explained by potential differences in exposure of endothelial cells to IFNγ 75,92 .…”

Section: Immune-vascular Crosstalkmentioning

confidence: 72%

“…A recent study induced IFNγ expression in murine fibrosarcoma and adenocarcinoma cells and selectively expressed IFNγ receptor in specific stromal cell types, including myeloid cells, fibroblasts, T cells, and endothelial cells; this study found that IFNγ directly promoted tumour vessel regression and blood flow arrest via its interactions with tumour endothelial cell IFNγ receptors, leading to intratumoral ischemia and subsequent collapse of the tumour 92 . The apparent discrepancy between this finding and the recent evidence that IFNγ promoted vessel normalization 75 could be explained by potential differences in exposure of endothelial cells to IFNγ 75,92 . The induction of IFNγ expression in tumour cells produced high systemic IFNγ concentrations (~10 ng/mL), which were maintained for a more extended period than the transient IFNγ elevation that can be elicited by adoptively transferred antigen-specific T cells 91 .…”

Section: Immune-vascular Crosstalkmentioning

confidence: 72%

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Improving immune–vascular crosstalk for cancer immunotherapy

Huang¹,

et al. 2018

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The vasculature of tumours is highly abnormal and dysfunctional. Consequently, immune effector cells have an impaired ability to penetrate into solid tumours and often exhibit compromised functions. Normalization of the tumour vasculature can enhance tissue perfusion and improve immune effector cell infiltration, leading to immunotherapy potentiation. However, recent studies, have demonstrated that stimulation of immune cell functions can also help to normalize tumour vessels. In this Opinion article, we propose that the reciprocal regulation between tumour vascular normalization and immune reprogramming forms a reinforcing loop that reconditions the tumour immune microenvironment to induce durable antitumour immunity. A deeper understanding of these pathways could pave the way for identifying new biomarkers and developing more effective combination treatment strategies for patients with cancer.

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Section: Immune-vascular Crosstalkmentioning

confidence: 72%

Section: Immune-vascular Crosstalkmentioning

confidence: 72%

Improving immune–vascular crosstalk for cancer immunotherapy

Huang¹,

et al. 2018

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“…Microhemorrhages were observed on MRI scans in other patients with severe neurotoxicity. A recent study in a murine tumor model found that IFN-γ and TNF-α contributed to tumor vessel regression and occlusion, and vascular burst, respectively (19); however, the relative contributions of distinct cytokines to BBB injury were not determined in these studies.…”

Section: Discussionmentioning

confidence: 97%

Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells

et al. 2017

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Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cells can be complicated by neurologic adverse events (AEs) in patients with refractory B cell malignancies. In 133 adults treated with CD19 CAR-T cells we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the CSF from high concentrations of systemic cytokines including IFN-γ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

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“…North and Havell (1988) demonstrated that a TNF-α-mediated antivascular effect was necessary for induction of tumor necrosis but was not sufficient to ensure continuous tumor regression (Havell et al, 1988), suggesting the involvement of additional vascular damaging factors. In this regard, IFNγ is known to possess potent antivascular effects (Kammertoens et al, 2017; Qin and Blankenstein, 2000). Moreover, some recent studies have revealed novel mechanisms by which T cell-derived IFNγ remodels the TME to promote antitumor immunity (Ayers et al, 2017; Sharma et al, 2018; Wang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

Habtetsion

Ding

et al. 2018

Cell Metabolism

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SUMMARY The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy.

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Tumour ischaemia by interferon-γ resembles physiological blood vessel regression

Cited by 197 publications

References 38 publications

Improving immune–vascular crosstalk for cancer immunotherapy

Improving immune–vascular crosstalk for cancer immunotherapy

Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells

Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

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