scholarly journals Characterization of the Tumor Microenvironment of Neurofibromatosis Type I Plexiform Neurofibromas

2020 ◽  
Vol 3 ◽  
Author(s):  
Abigail Chmiel ◽  
Steven Rhodes ◽  
Steve Angus ◽  
Yongzheng He ◽  
Quingbo Lu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Lineage ◽  
Neurofibromatosis Type ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Type I Ifn ◽  
Plexiform Neurofibromas ◽  
Reference Matrix ◽  
Macrophage Lineage

Background/Objective:  Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. Patients with NF1 develop tumors of the peripheral nervous system called plexiform neurofibromas (PNs). These histopathologically complex tumors are composed of various immune and inflammatory cells. Mast cells have previously been identified as one key immune cell lineage underpinning PN initiation and progression, however new technologies leveraging RNA-sequencing (RNAseq) allow for the broad and systematic characterization of the PN tumor microenvironment. Here we utilized these tools to delineate PN cellular composition.  Methods:  RNA seq was performed on murine wild type (n=6) and PN (n=6) tissues. We utilized CIBERSORT to profile the cellular constituents of the PN microenvironment. CIBERSORT is a deconvolution method that uses a reference matrix to estimate the relative proportions of various cell types. Statistical analyses were performed on cell lineage subtypes delineated by CIBERSORT. We further performed a Gene Set Enrichment Analysis (GSEA) to identify which pathways and cytokines might be upregulated in PNs.   Results:  Using a murine reference matrix, the macrophage lineage, M0 (p = 0.072), M1 (p = 0.1), were upregulated in PNs (n=6) compared to WT (n=6). A human reference matrix showed M2 (p=0.025) to be upregulated in PNs. GSEA showed IL-1, IL-6, IL-8, TNF and Type I IFN and cytokine secretion to be upregulated in PNs compared to WT.   Conclusion:  Macrophages were among the most upregulated components of the NF1 tumor microenvironment and upregulation of IL-1, IL-6, IL-8, TNF and Type I IFN production may be contributing to inflammation that is critical in the initiation and progression of PNs.    Scientific/Clinical/Policy Impact and Implications:  Pharmacotherapies that can target the macrophage lineage and/or aforementioned cytokines may have utility in the treatment of PNs. Further studies are necessary to evaluate this hypothesis. 

scholarly journals Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

2017 ◽  
Vol 114 (51) ◽  
pp. E10981-E10990 ◽  
Author(s):  
Meredith L. Stone ◽  
Katherine B. Chiappinelli ◽  
Huili Li ◽  
Lauren M. Murphy ◽  
Meghan E. Travers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Histone Deacetylase Inhibitors ◽  
Unmet Need ◽  
Tumor Burden ◽  
Epigenetic Therapy ◽  
Type I ◽  
Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi181-vi181
Author(s):  
Yuanfan Yang ◽  
Michael Brown ◽  
Kevin Stevenson ◽  
Giselle lopez ◽  
Reb Kornahrens ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Cd8 T Cell ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Acute Type ◽  
Type I Ifn ◽  
Term Survival

Abstract Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.

scholarly journals Overproduction of IL-6 and Type-I IFN in a Lethal Case of Chikungunya Virus Infection in an Elderly Man During the 2017 Italian Outbreak

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Francesca Colavita ◽  
Serena Vita ◽  
Eleonora Lalle ◽  
Fabrizio Carletti ◽  
Licia Bordi ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Strong Increase ◽  
Type I ◽  
Type I Ifn ◽  
Chikv Infection ◽  
Clinical Presentations ◽  
Abnormal Pattern ◽  
Disease Analysis

Abstract Chikungunya fever is caused by Chikungunya virus (CHIKV) and is generally considered a self-limiting disease. However, severe clinical presentations with a high mortality rate have been reported in association with underlying medical conditions. This study reports the molecular characterization of the virus and an abnormal pattern of circulating cytokines in a unique lethal CHIKV case during the 2017 outbreak in Italy, which involved an elderly patient with underlying cardiac disease. Analysis of inflammatory cytokines revealed a strong increase of interferon (IFN)-α and IFN-β, as well as interleukin-6, suggesting a possible role of type-I IFN in the cytokine storm, which may be correlated with unfavorable prognosis of CHIKV infection.

scholarly journals STING contributes to anti-glioma immunity via triggering type-I IFN signals in the tumor microenvironment

2014 ◽  
Vol 2 (Suppl 3) ◽  
pp. P228 ◽  
Author(s):  
Takayuki Ohkuri ◽  
Arundhati Ghosh ◽  
Akemi Kosaka ◽  
Jianzhong Zhu ◽  
Maki Ikeura ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Type I ◽  
Type I Ifn

scholarly journals Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

2021 ◽  
Author(s):  
Jennifer L. Green ◽  
Robin Osterhout ◽  
Amy L. Klova ◽  
Carsten Merkwirth ◽  
Scott R.P. McDonnell ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Molecular Characterization ◽  
Type I ◽  
Type I Ifn ◽  
Bladder Cancer Cells

scholarly journals Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuezhi Cao ◽  
Yong Liang ◽  
Zhenxiang Hu ◽  
Huiyu Li ◽  
Jiaming Yang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Responses ◽  
Half Life ◽  
Tumor Targeting ◽  
Type I Interferon ◽  
Therapy Resistance ◽  
Type I ◽  
Type I Ifn ◽  
Targeting Effect

AbstractType I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.

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