scholarly journals 642 Decreased host PKC-delta is associated with the T cell-inflamed tumor microenvironment and improves anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A671-A671
Author(s):  
Kyle Cron ◽  
Ayelet Sivan ◽  
Keston Aquino-Michaels ◽  
Emily Higgs ◽  
Jessica Fessler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Immune Response ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Regulatory Genes ◽  
Immune Gene ◽  
Loss Of Function ◽  
Pkc Delta

BackgroundFavorable clinical responses to immunotherapy have been correlated with a T cell-inflamed tumor microenvironment. The degree of spontaneous immune infiltration in tumors varies widely between individual patients. We hypothesized that germline polymorphisms in immune regulatory genes may affect the host immune response to solid tumors, similar to their influence on autoimmune susceptibility.MethodsMelanoma TCGA RNAseq and germline SNP data were utilized to identify germline polymorphisms associated with the magnitude of an immune gene signature score. The top GWAS hit associated with increased immune gene expression in melanoma was SNP rs1483185 (p = 8.812e-08, Bonferroni corrected <0.05), within the PKC-delta gene. Using a lymphoblastic cell line GTEX database, this SNP was associated with lower expression PKC-delta, implying a loss of function phenotype. Germline mutations in PKC-delta had previously been associated with familial lupus. To study the role of PKC-delta in anti-tumor immunity, knockout hematopoietic cells and conditional knockout mice were utilized, and implanted tumors were monitored along with detailed immune response analysis.ResultsB16.SIY tumors grew more slowly in chimeras reconstituted with PKC-delta-/- bone marrow compared to WT bone marrow, and this effect was dependent on CD8-beta+ cells. T cell priming in the tumor-draining lymph node was comparable in WT and KO hosts. However, tumors in PKC-delta-/- bone marrow chimeras had increased numbers of CD8+ T cells in the tumor at endpoint, and also responded better to anti-PD-L1 therapy. Single cell RNAseq of the tumor microenvironment revealed that PKC-delta loss primarily altered gene expression in myeloid cell subsets, leading to to increased expression of M1 associated genes and decreased expression of M2 associated genes in PKC-delta-/- chimeras. To follow up further, a conditional PKC-delta KO mouse was developed and crossed to the hematopoietic Vav1-iCre and also to LysM-Cre transgenic mice. In both instances, immune-mediated tumor control was improved, demonstrating that loss of PKC-delta in the myeloid compartment is sufficient to recapitulate the phenotype.ConclusionsOur results demonstrate that germline variants in immune regulatory genes can profoundly affect anti-tumor immunity and the efficacy of PD-1/PD-L1 blockade. In particular, the myeloid-expressed molecule PKC-delta plays an important regulatory role such that decreased expression/activity mediates improved anti-tumor immunity by altering the M1/M2 ratio. The development of pharmacologic approaches to phenocopy this loss of function phenotype may be attractive to pursue as a novel therapeutic strategy.Ethics ApprovalUniversity of Chicago IRB Protocol 15-0837

scholarly journals Hiding the road signs that lead to tumor immunity

2011 ◽  
Vol 208 (10) ◽  
pp. 1937-1940 ◽  
Author(s):  
David A. Schaer ◽  
Alexander M. Lesokhin ◽  
Jedd D. Wolchok
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Tumor Immunity ◽  
New Work ◽  
The Road ◽  
T Cell Infiltration ◽  
Road Signs

Tumors exploit many strategies to evade T cell–mediated destruction. For example, tumors can prevent T cell infiltration by modifying gene expression in the endothelial cells and pericytes that form their vasculature. New work showing that the T cell–attracting chemokine CCL2 can be posttranslationally modified in the tumor microenvironment adds another mechanism to the already formidable arsenal of immunoevasion tactics used by solid tumors.

Characterization of anti-CD19 chimeric antigen receptor (CAR) T cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
Jerome Galon ◽  
John Rossi ◽  
Sarah Turcan ◽  
Corinne Danan ◽  
Frederick Lundry Locke ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Objective Response ◽  
Gene Signature ◽  
Fold Change ◽  
Immune Gene ◽  
Car T Cell ◽  
Car T

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.

253 Anti-TIGIT antibodies require enhanced FcγR co-engagement for optimal T and NK cell-dependent anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A275-A275
Author(s):  
Rebecca Ward ◽  
Elena Paltrinieri ◽  
Marilyn Marques ◽  
Priyadarshini Iyer ◽  
Sylvia Dietrich ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Control ◽  
Tumor Bearing ◽  
Anti Tumor Activity ◽  
Ct26 Tumor ◽  
Dependent Mechanism

BackgroundT-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an important negative regulator of the immune response to cancer that contributes to resistance/relapse to anti-PD-1 therapy.1 In clinical trials, anti-human (h) TIGIT antibodies have shown promising activity in combination with anti-PD-1/PD-L1 antibodies for the treatment of various solid tumors.2 However, the optimal format for anti-TIGIT antibodies remains controversial. Here we describe a novel Fcγ receptor (FcγR)-dependent mechanism of action that is critical for enhancing T and NK cell anti-tumor immunity, and, further informs on the optimal design of anti-TIGIT antibodies.MethodsWe investigated a panel of Fc-silent, Fc-competent, and Fc-engineered anti-mouse (m) TIGIT antibody variants in syngeneic murine CT26 tumor-bearing or B16F10 pseudo-metastases models. To further elucidate the relative contribution of T and NK cells in controlling tumor growth, we assessed the activity of Fc-engineered anti-TIGIT antibodies in NK cell-depleted or T cell-deficient (Nu-Foxn1nu) CT26 tumor-bearing mice. Immune-related pharmacodynamic changes in the tumor microenvironment were assessed by flow cytometry. We further validated these findings in primary human T and NK cell activation assays using Fc-engineered anti-human TIGIT antibodies.ResultsThe Fc-engineered anti-mTIGIT antibody, which demonstrates enhanced binding to mouse FcγRIV, was the only variant to deliver single agent anti-tumor activity. The Fc-enhanced variant outperformed the Fc-competent variant while the Fc-inert variant had no anti-tumor activity. Tumor control by anti-mTIGIT antibodies was not dependent on Treg depletion, but rather on increased frequency of CD8+ T cells and activated NK cells (Ki67, IFNγ, CD107a and TRAIL) in the tumor microenvironment. Concordant with observations in the mouse, Fc-engineered anti-hTIGIT antibodies with improved binding to FcγRIIIA demonstrate superior T and NK cell activation in PBMC-based assays compared to a standard hIgG1 variant. Notably, superior activity of the Fc-engineered anti-hTIGIT antibody was observed from PBMC donors that express either high or low affinity FcγRIIIA. Blockade of FcγRIIIA or depletion of CD14+ and CD56+ cells reduced the functional activity of the Fc-enhanced anti-TIGIT antibody, confirming the requirement for FcγR co-engagement to maximize T cell responses.ConclusionsOur data demonstrate the importance of FcγR co-engagement by anti-TIGIT antibodies to promote immune activation and tumor control. First generation anti-TIGIT antibodies are not optimally designed to co-engage all FcγRIIIA variants. However, Fc-enhanced anti-TIGIT antibodies unlock a novel FcγR-dependent mechanism of action to enhance T and NK cell-dependent anti-tumor immunity and further improve therapeutic outcomes.ReferencesJohnston RJ, et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26:923–37.Rodriguez-Abreu D, et al., Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). Journal of Clinical Oncology 2020; 38:15_suppl, 9503–9503.

scholarly journals 644 Tumor-mediated suppressive signaling and hypoxia supports altered chromatin landscapes that limit the transcriptional and functional potential of terminal T cell exhaustion

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A673-A673
Author(s):  
Rhodes Ford ◽  
Natalie Rittenhouse ◽  
Nicole Scharping ◽  
Paolo Vignali ◽  
Greg Delgoffe ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Histone Modifications ◽  
Cd8 T Cells ◽  
Tumor Hypoxia ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

BackgroundCD8+ T cells are a fundamental component of the anti-tumor response; however, tumor-infiltrating CD8+ T cells (TIL) are rendered dysfunctional by the tumor microenvironment. CD8+ TIL display an exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors (IRs), such as PD-1 and Tim-3. The acquisition of IRs mark the progression of dysfunctional TIL from progenitors (PD-1Low) to terminally exhausted (PD-1+Tim-3+). How the chromatin landscape changes during this progression has not been described.MethodsUsing a low-input ChIP-based assay called Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we have profiled the histone modifications at the chromatin of tumor-infiltrating CD8+ T cell subsets to better understand the relationship between the epigenome and the transcriptome as TIL progress towards terminal exhaustion.ResultsWe have identified two epigenetic characteristics unique to terminally exhausted cells. First, we have identified a unique set of genes, characterized by active histone modifications that do not have correlated gene expression. These regions are enriched for AP-1 transcription factor motifs, yet most AP-1 family factors are actively downregulated in terminally exhausted cells, suggesting signals that promote downregulation of AP-1 expression negatively impacts gene expression. We have shown that inducing expression of AP-1 factors with a 41BB agonist correlates with increased expression of these anticorrelated genes. We have also found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both active (H3K4me3) and repressive (H3K27me3) chromatin modifications that inhibit gene expression. These bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia, which is necessary and sufficient to promote downregulation of bivalent genes.ConclusionsOur study defines for the first time the roles of costimulation and the tumor microenvironment in driving epigenetic features of terminally exhausted tumor-infiltrating T cells. These results suggest that terminally exhausted T cells have genes that are primed for expression, given the right signals and are the basis for future work that will elucidate that factors that drive progression towards terminal T cell exhaustion at the epigenetic level and identify novel therapeutic targets to restore effector function of tumor T cells and mediate tumor clearance.

scholarly journals Altered Expression of Hematopoiesis Regulatory Genes in the Bone Marrow Mesenchymal Stem Cells of Patients of Aplastic Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3904-3904
Author(s):  
Soniya Nityanand ◽  
Naresh Kumar Tripathy ◽  
Chandra Prakash Chaturvedi ◽  
Ekta Minocha ◽  
Akhilesh Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Fold Increase ◽  
Regulatory Genes ◽  
Control Group ◽  
Medical Sciences ◽  
Post Graduate ◽  
Tnf Α ◽  
Post Graduate Institute

Abstract Mesenchymal stem cells (MSC) are an important component of the hematopoietic niche in the bone marrow (BM) and regulate hematopoiesis by producing a variety of cytokines and growth factors. In aplastic anemia (AA), most of the studies have attributed the reduced hematopoiesis to a defect in hematopoietic stem cells (HSC) and limited data is available on the role of BM-MSC in AA. Therefore, the objective of the present study was to evaluate the expression of hematopoiesis regulatory genes, viz. granulocyte colony stimulating factor (G-CSF), stromal cell derived factor (SDF-1), stem cell factor (SCF), tumor necrosis factor-alpha (TNF-α) macrophage inflammatory protein-1 alpha (MIP-1α) and transforming growth factor-beta (TGF-β) in BM-MSC of patients with AA and compare it with BM-MSC of control group. Twenty patients of idiopathic acquired AA with a median age of 25.5 years (range: 12-64 years) were included in the study. The control group consisted of 10 healthy volunteers and 10 patients with iron deficiency anemia or immune thrombocytopenic purpura. The median age of the control group was 20 years (range: 11-62 years). The BM-MSC were isolated and cultured as per protocol standardized and previously published by us. Third passage cells were used in the study. The MSC were characterized both by their phenotypic markers and by their ability to differentiate into adipogenic and osteogenic lineages. The expression of hematopoiesis regulatory genes was studied by real-time quantitative polymerase chain reaction (qRT-PCR). The GAPDH was used as the housekeeping gene to normalize the transcript levels and the fold change in the gene expression was calculated by 2-ΔΔCtmethod. The BM-MSC of AA patients and controls had similar morphology and expression of mesenchymal markers CD73, CD105, CD90 and CD166, absence of expression of hematopoietic markers CD13, CD34 and CD45 and of HLA-DR. However, the BM-MSC of AA patients exhibited a higher adipogenic and a lower osteogenic differentiation in comparison to those of controls. Further, the BM-MSC of AA patients in comparison to those of control group, had a higher expression of G-CSF (fold increase: 1.99; p<0.0001), SDF-1 (fold increase: 1.37; p<0.01) and TNF-α (fold increase: 10.68; p<0.0001) and a very low expression of MIP-1α (fold decease: 50.0; p<0.0001) transcripts. The expression of SCF and TGF-β transcripts were comparable in the BM-MSC of both the groups (p>0.05). Though AA patients have been shown to have elevated levels of G-CSF in the peripheral blood and BM but there is only one previous report on G-CSF gene expression in BM-MSC of AA, in which a higher expression was observed and thus corroborates with our data. There is no data available on SDF-1 levels in the peripheral blood and bone marrow of AA patients. We have observed higher gene expression of SDF-1 in BM-MSC of AA patients. The higher expression of G-CSF and SDF-1, pro-hematopoietic factors, in AA may be due to a compensatory response of the BM stroma to boost the hematopoiesis. Our observation of higher TNF-α gene expression in BM-MSC corroborates with previous reports on higher levels of this anti-hematopoietic cytokine in the BM plasma of patients with AA and indicates that MSC could contribute to the increase in the TNF-α level in the BM of AA patients. A conspicuous observation of our study was a markedly decreased expression of MIP-1α gene in BM-MSC of AA and to the best of our knowledge this is the first report on MIP-1α in AA. MIP-1α is a chemokine which has been shown to inhibit proliferation of HSC in vitro and thus may help to maintain HSC in an undifferentiated state. Furthermore, MIP-1α has also been reported to mediate interaction of HSC with stromal cells in BM and may have a role in supporting hematopoiesis. Its precise role in AA needs to be studied further. We are currently studying the levels of these cytokines/growth factors in the BM plasma of the same cohort of AA patients and controls and the data will be presented. Our study thus shows that BM-MSC of AA patients have altered expression of hematopoiesis regulatory genes which may contribute to the pathobiology of the disease. Disclosures Nityanand: Sanjay Gandhi Post Graduate Institute of Medical Sciences: Employment, Research Funding. Tripathy:Sanjay Gandhi Post Graduate Institute of Medical Sciences: Employment. Chaturvedi:Dept of Biotechnology, Govt of India: Employment. Minocha:Dept of Science and Technology, Govt of India: Other: PhD scholarship. Sharma:Sanjay Gandhi Post Graduate Institute of Medical Sciences: Employment. Rahman:SGPGI, Lucknow , India: Employment, Research Funding.

scholarly journals The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhengguo Wu ◽  
Shang Li ◽  
Xiao Zhu
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Checkpoint Inhibitors ◽  
The Body ◽  
Research Progress ◽  
Effective Population ◽  
Cell Components

Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

scholarly journals A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

2021 ◽  
Author(s):  
Alberto Gomez-Carballa ◽  
Irene Rivero-Calle ◽  
Jacobo Pardo-Seco ◽  
Jose Gomez-Rial ◽  
Carmen Rivero-Velasco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Local Level ◽  
Antiviral Response ◽  
Innate Immune ◽  
Nasal Epithelium ◽  
Severe Illness ◽  
Immune Gene ◽  
Innate Antiviral Response ◽  
Immune Related Genes

Background: COVID-19 symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences. Methods and findings: We carried out a multi-tissue (nasal, buccal and blood; n = 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. We then used a differential expression approach and pathways analysis to detect tissue specific immune severity signals in COVID-19 patients. Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were shown in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis. Conclusions: We found severity-related signatures in patient tissues mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.

Resetting the tumor microenvironment to favor anti-tumor immunity after local ablation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2561-2561
Author(s):  
Corrine A. Nief ◽  
Júlia Sroda Agudogo ◽  
Alana Gonzales ◽  
Rebecca A. Previs ◽  
Smita K Nair ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Low Dose ◽  
Tumor Response ◽  
Surgical Excision ◽  
Tumor Ablation ◽  
Local Ablation

2561 Background: Percutaneous tumor ablation is a non-surgical method of tumor destruction that leaves necrotic tumor debris in situ. Tumor associated antigens released after ablation have the potential to initiate a systemic anti-tumor immune response, however the hostile tumor microenvironment hinders antigen presentation and T cell activity. We hypothesized that resetting the tumor microenvironment with oral sodium bicarbonate to decrease tumor acidity and low-dose cyclophosphamide to deplete pro-tumor immune cells would improve the ability of ablation to initiate anti-tumor immunity. Methods: Tumor growth, overall survival, and metastatic burden was assessed in orthotopic tumor models of triple-negative breast cancer (67NR, 4T1, and E0771). Tumor ablation was performed on palpable tumors using percutaneous ethanol injection (PEI) with 6% ethylcellulose to improve retention in the tumor. Surgical excision was used as a negative control to test the role of in situ tumor debris. Before ablation mice were placed on 200 mM of sodium bicarbonate (SB) in their drinking water and received a single intraperitoneal injection of 200 mg/kg of cyclophosphamide (CP). Mice surviving to 60 days after tumor implant without a primary tumor or signs of metastases were considered "cured" and re-challenged with 50e5 tumor cells in the contralateral mammary pad. T cell dependance was assessed with in vivo CD8 depletions. Results: The combination of PEI+SB+CP produced a potent anti-tumor response, curing a majority of mice (5/7 of E0771, 8/12 of 67NR, 7/12 of 4T1). No mice were cured using PEI alone, SB alone, CP alone, or any combination of two therapies (0/51 of E0771, 0/73 of 67NR, 0/75 of 4T1,). Re-challenge tumor growth was hindered in mice cured with PEI+SB+CP. Mice receiving PEI+SB+CP had significantly less metastases and lived longer than mice receiving surgical excision alone or surgical excision with SB+CP. Additionally the anti-metastatic response of PEI+SB+CP was undone when CD8+ T cells were depleted. Conclusions: Here the anti-tumor response of local ablation produced by PEI was enhanced by priming the tumor with low-dose CP and oral SB in metastatic breast cancer. These results suggest that tumor ablation with CP and SB can create a T cell dependent, personalized immune response to a tumor using only low-cost, easily accessible supplies, and the host’s own tumor.

scholarly journals IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 326
Author(s):  
Anurag R. Mishra ◽  
Siddappa N. Byrareddy ◽  
Debasis Nayak
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Vesicular Stomatitis Virus ◽  
Antiviral Response ◽  
Type I ◽  
Immune Gene ◽  
Antiviral Immune Response ◽  
Virus Challenge ◽  
Vesicular Stomatitis ◽  
Ifn Γ

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

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