Publications by authors named "Bellur S Prabhakar"

112 Publications

Combination Immunotherapy With LIGHT and Interleukin-2 Increases CD8 Central Memory T-Cells In Vivo.

J Surg Res 2021 Feb 22;263:44-52. Epub 2021 Feb 22.

Division of Surgical Oncology, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois. Electronic address:

Background: The generation of long-term durable tumor immunity and prolonged disease-free survival depends on the ability to generate and support CD8+ central memory T-cells. Microsatellite-stable colon cancer is resistant to currently available immunotherapies; thus, development of novel mechanisms to increase both lymphocyte infiltration and central memory formation are needed to improve outcomes in these patients. We have previously demonstrated that both interleukin-2 (IL-2) and LIGHT (TNFSF14) independently enhance antitumor immune responses and hypothesize that combination immunotherapy may increase the CD8+ central memory T-cell response.

Methods: Murine colorectal cancer tumors were established in syngeneic mice. Tumors were treated with control, soluble, or liposomal IL-2 at established intervals. A subset of animal tumors overexpressed tumor necrosis superfamily factor LIGHT (TNFSF14). Peripheral blood, splenic, and tumor-infiltrating lymphocytes were isolated for phenotypic studies and flow cytometry.

Results: Tumors exposed to a combination of LIGHT and IL-2 experienced a decrease in tumor size compared with IL-2 alone that was not demonstrated in wild-type tumors or between other treatment groups. Combination exposure also increased splenic central memory CD8+ cells compared with IL-2 administration alone, while not increasing tumor-infiltrating lymphocytes. In the periphery, the combination enhanced levels of circulating CD8 T-cells and central memory T-cells, while also increasing circulating T-regulatory cells.

Conclusions: Combination of IL-2, whether soluble or liposomal, with exposure to LIGHT results in increased CD8+ central memory cells in the spleen and periphery. New combination immunotherapy strategies that support both effector and memory T-cell functions are critical to enhancing durable antitumor responses and warrant further investigation.
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http://dx.doi.org/10.1016/j.jss.2021.01.010DOI Listing
February 2021

Epidemiology of out-of-Hospital Cardiac Arrests, knowledge of cardiovascular disease and risk factors in a regional setting in India: The Warangal Area out-of-hospital Cardiac Arrest Registry (WACAR).

Indian Heart J 2020 Nov-Dec;72(6):517-523. Epub 2020 Oct 20.

Departments of Global Health & Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.

Objective: Out-of-Hospital Cardiac Arrest (OHCA) is a global public health problem. There is inadequate data on OHCA in India. The Warangal Area out-of-hospital Cardiac Arrest Registry (WACAR) was planned to understand OHCA in a regional setting in India.

Methods: WACAR is a prospective one-year observational cohort study of OHCA in the Warangal area, Telangana, India. The study included 814 subjects of OHCA of presumed cardiac etiology brought to the Mahatma Gandhi Memorial Hospital during January 1, 2018, and December 31, 2018. The data collected included; standard Utstein variables with additional data on clinical characteristics (modified Utstein template).

Results: The majority of OHCA subjects were male with a median age of 60 years, and mostly occurring in residential locations within 1 h of onset of symptoms. Individuals with knowledge of CVD risk factors were more likely to report symptoms before OHCA. Data on resuscitation characteristics were inadequate.

Conclusions: The WACAR study provides baseline data regarding OHCA in a regional setting in India. The study demonstrated barriers involving data collection, patient knowledge of CVD risk factors and disease, and access to healthcare, which; impacted the data registry.
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http://dx.doi.org/10.1016/j.ihj.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772591PMC
October 2020

Induction of Antigen-Independent Proliferation of Regulatory T-Cells by TNF Superfamily Ligands OX40L and GITRL.

Methods Mol Biol 2021 ;2248:63-71

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.

TNF receptor superfamily comprises many T-cell costimulatory receptors, including TNFRSF1, TNFRSF2, TNFRSF4 (OX40), TNFRSF9 (4-1BB), TNFRSF18 (GITR), and TNFRSF7 (CD27). Signaling through these costimulatory stimulatory receptors can promote conventional T-cell (Tconv) proliferation, and effector functions in an antigen-dependent manner. Thus, agonistic antibodies and ligands for OX40, 4-1BB, GITR, and CD27 have been tested for inducing T-cell-mediated antitumor responses in several cancers. However, recently emerging reports show critical role for TNFR signaling in regulatory T-cell (Treg) differentiation and expansion, which might suppress effector T-cell proliferation and functions. Here, we show preferential over expression of TNFR2, OX40, 4-1BB, and GITR in Treg cells over Tconv cells, and the ability of OX40L and GITRL to induce selective proliferation of Treg cells, but not Tconv cells, in an antigen-independent manner. We describe the standard protocols used for Affymetrix gene expression profiling, T-cell isolation, and Cell Trace Violet-based cell proliferation assay.
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http://dx.doi.org/10.1007/978-1-0716-1130-2_4DOI Listing
April 2021

Post-translational modifications contribute to neoepitopes in Type-1 diabetes: Challenges for inducing antigen-specific tolerance.

Biochim Biophys Acta Proteins Proteom 2020 10 26;1868(10):140478. Epub 2020 Jun 26.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, United States of America. Electronic address:

Type-1 Diabetes (T1D) is the major autoimmune disease affecting the juvenile population in which insulin-producing pancreatic β-cells are destroyed by self-reactive T-cells and B-cells. Emerging studies have identified the presence of autoantibodies and altered T-cell reactivity against several autoantigens in individuals who are at risk of developing T1D even before the clinical onset of diabetes. Whilst these findings could lead to the development of predictive biomarkers for early diagnosis, growing evidence on the generation of neoepitopes, epitope spreading and diverse antigen repertoire in T1D poses a major challenge for developing approaches to induce antigen-specific tolerance. Mechanisms of neoepitope generation include post-translational modifications of existing epitopes, aberrant translational products, peptide fusion, and differences in MHC binding registers. Here, we focus our discussion on how post-translational modifications can give rise to immunogenic neoepitopes in T1D and present our perspective on how it could affect the development of therapeutic approaches to induce antigen-specific tolerance.
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http://dx.doi.org/10.1016/j.bbapap.2020.140478DOI Listing
October 2020

Oncolytic adenovirus encoding LIGHT (TNFSF14) inhibits tumor growth via activating anti-tumor immune responses in 4T1 mouse mammary tumor model in immune competent syngeneic mice.

Cancer Gene Ther 2020 Dec 20;27(12):923-933. Epub 2020 Apr 20.

Anhui Medical University, Hefei, 230032, Anhui, PR China.

LIGHT, also known as tumor-necrosis factor (TNF) superfamily member 14 (TNFSF14), is predominantly expressed on activated immune cells and some tumor cells. LIGHT is a pivotal regulator both for recruiting and activating immune cells in the tumor lesions. In this study, we armed human telomerase reverse transcriptase (TERT) promoter controlled oncolytic adenovirus with LIGHT to generate rAd.Light. rAd.Light effectively transduced both human and mouse breast tumor cell lines in vitro, and expressed LIGHT protein on the surface of tumor cells. Both rAd.Null, and rAd.Light could replicate in human breast cancer cells, and produced cytotoxicity to human and mouse mammary tumor cells. rAd.Light induced apoptosis resulting in tumor cell death. Using a subcutaneous model of 4T1 cells in BALB/c mice, rAd.Light was delivered intratumorally to evaluate the anti-tumor responses. Both rAd.Light and rAd.Null significantly inhibited the tumor growth, but rAd.Light produced much stronger anti-tumor effects. Histopathological analysis showed the infiltration of T lymphocytes in the tumor tissues. rAd.Light also induced stronger cellular apoptosis than rAd.Null in the tumors. Interestingly, on day 15, compared to rAd.Null, there was a significant reduction of Tregs following rAd.Light treatment. rAd.Light significantly increased Th1 cytokine interleukin (IL)-2 expression, and reduced Th2 cytokines expression, such as transforming growth factor β (TGF-β) and IL-10 in the tumors. These results suggest rAd.Light induced activation of anti-tumor immune responses. In conclusion, rAd.Light produced anti-tumor effect in a subcutaneous model of breast cancer via inducing tumor apoptosis and evoking strong anti-tumor immune responses. Therefore, rAd.Light has great promise to be developed as an effective therapeutic approach for the treatment of breast cancer.
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http://dx.doi.org/10.1038/s41417-020-0173-zDOI Listing
December 2020

OX40L-JAG1-Induced Expansion of Lineage-Stable Regulatory T Cells Involves Noncanonical NF-κB Signaling.

J Immunol 2019 12 8;203(12):3225-3236. Epub 2019 Nov 8.

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612;

Foxp3T regulatory cells (Tregs) control autoimmune response by suppressing proliferation and effector functions of self-reactive Foxp3CD4/CD8 T cells and thereby maintain the critical balance between self-tolerance and autoimmunity. Earlier, we had shown that OX40L-JAG1 cosignaling mediated through their cognate receptors OX40 and Notch3 preferentially expressed on murine Tregs can selectively induce their proliferation in the absence of TCR stimulation. However, the differential molecular mechanisms regulating TCR-independent versus TCR-dependent Treg proliferation and lineage stability of the expanded Tregs remained unknown. In this study, we show that OX40L-JAG1 treatment induced TCR-independent proliferation of Tregs in the thymus and periphery. The use of Src kinase inhibitor permitted us to demonstrate selective inhibition of TCR-dependent T cell proliferation with little to no effect on OX40L-JAG1-induced TCR-independent Treg expansion in vitro, which was critically dependent on noncanonical NF-κB signaling. OX40L-JAG1-expanded Tregs showed sustained lineage stability as indicated by stable demethylation marks in Treg signature genes such as and Furthermore, OX40L-JAG1 treatment significantly increased CTLA4 and TIGIT Tregs and alleviated experimental autoimmune thyroiditis in mice. Relevance of our findings to humans became apparent when human OX40L and JAG1 induced TCR-independent selective expansion of human Tregs in thymocyte cultures and increased human Tregs in the liver tissue of humanized NSG mice. Our findings suggest that OX40L-JAG1-induced TCR-independent Treg proliferation is a conserved mechanism that can be used to expand lineage-stable Tregs to treat autoimmune diseases.
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http://dx.doi.org/10.4049/jimmunol.1900530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904432PMC
December 2019

Vemurafenib may overcome TNF-related apoptosis-inducing ligand (TRAIL) resistance in anaplastic thyroid cancer cells.

Endocrine 2020 01 3;67(1):117-123. Epub 2019 Aug 3.

Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy.

Purpose: Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206).

Methods: Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C).

Results: C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model.

Conclusions: TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.
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http://dx.doi.org/10.1007/s12020-019-02028-2DOI Listing
January 2020

An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy.

Hum Gene Ther 2019 09 1;30(9):1117-1132. Epub 2019 Jul 1.

Gene Therapy Program, Department of Medicine, NorthShore Research Institute, an Affiliate of the University of Chicago, Evanston, Illinois.

In an effort to develop a new therapy for cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated protein (anti-CTLA-4) responses, we have created a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble transforming growth factor receptor II fused with human IgG Fc fragment (sTGFβRIIFc) gene. Infection of breast and renal tumor cells with rAd.sT produced sTGFβRIIFc protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1 breast tumor model, intratumoral delivery of rAd.sT inhibited both tumor growth and lung metastases. rAd.sT downregulated the expression of several transforming growth factor β (TGFβ) target genes involved in tumor growth and metastases, inhibited Th2 cytokine expression, and induced Th1 cytokines and chemokines, and granzyme B and perforin expression. rAd.sT treatment also increased the percentage of CD8 T lymphocytes, promoted the generation of CD4 T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4 T lymphocytes, and promoted differentiation and maturation of antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal tumor model, similar therapeutic effects and immune activation results were observed. In the 4T1 mammary tumor model, rAd.sT improved the inhibition of tumor growth and lung and liver metastases by anti-PD-1 and anti-CTLA-4 antibodies. Analysis of the human breast and kidney tumors showed that a significant number of tumor tissues expressed high levels of TGFβ and TGFβ-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4 therapy for treating breast and kidney cancers.
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http://dx.doi.org/10.1089/hum.2019.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761593PMC
September 2019

MADD silencing enhances anti-tumor activity of TRAIL in anaplastic thyroid cancer.

Endocr Relat Cancer 2019 06;26(6):551-563

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

ATC is an aggressive disease with limited therapeutic options due to drug resistance. TRAIL is an attractive anti-cancer therapy that can trigger apoptosis in a cancer cell-selective manner. However, TRAIL resistance is a major clinical obstacle for its use as a therapeutic drug. Previously, we demonstrated that MADD is a cancer cell pro-survival factor that can modulate TRAIL resistance. However, its role, if any, in overcoming TRAIL resistance in ATC is unknown. First, we characterized ATC cell lines as either TRAIL resistant, TRAIL sensitive or moderately TRAIL sensitive and evaluated MADD expression/cellular localization. We determined the effect of MADD siRNA on cellular growth and investigated its effect on TRAIL treatment. We assessed the effect of combination treatment (MADD siRNA and TRAIL) on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels. The effect of combination treatment on tumor growth was assessed in vivo. We found increased levels of MADD in ATC cells relative to Nthy-ori 3-1. MADD protein localizes in the cytosol (endoplasmic reticulum and Golgi body) and membrane. MADD knockdown resulted in spontaneous cell death that was synergistically enhanced when combined with TRAIL treatment in otherwise resistant ATC cells. Combination treatment resulted in a significant reduction in MMP and enhanced generation of ROS indicating the putative mechanism of action. In an orthotopic mouse model of TRAIL-resistant ATC, treatment with MADD siRNA alone reduced tumor growth that, when combined with TRAIL, resulted in significant tumor regressions. We demonstrated the potential clinical utility of MADD knockdown in sensitizing cells to TRAIL-induced apoptosis in ATC.
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http://dx.doi.org/10.1530/ERC-18-0517DOI Listing
June 2019

Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer.

Cell Death Dis 2019 02 13;10(2):145. Epub 2019 Feb 13.

Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Anaplastic Thyroid Cancer (ATC) is an aggressive malignancy with limited therapeutic options and dismal patient survival. We have previously shown MADD to be differentially overexpressed in multiple cancer histologies and to contribute to tumor cell growth and survival. Therefore, we targeted MADD by gene silencing, explored its effect on cellular proliferation and metastases and examined its therapeutic potential in an orthotopic ATC model in athymic nude mice. When compared to untreated control and scramble siRNA, MADD siRNA treatment inhibited the proliferative capacity of 8505C, C643 and HTH7 cells in vitro and 8505C-derived-orthotopic tumor growth in vivo. MADD ablation caused a significant reduction in cellular migration and invasion potential; clonogenic capacity; as well as, mitochondrial length and potential in vitro. This MADD siRNA-induced anti-migratory/invasive effect corresponded with inhibition of epithelial-mesenchymal transition (EMT) and Wnt signaling. Mechanistically, MADD siRNA inhibited TNFα induced activation of pERK, pGSK3β and β-catenin, suggesting that MADD knockdown might exert its anti-migratory/invasive effects, by blocking TNFα/ERK/GSK3β axis. MADD siRNA can inhibit β-catenin nuclear translocation and consequently, the expression of its target genes in ATC cells. In in vivo experiments, along with tumor regression, MADD siRNA treatment also decreased evidence of lung metastases. Immunohistochemically, MADD siRNA-treated tumor tissues exhibited a reduction in Ki67 and N-Cadherin expression, and an increase in E-Cadherin expression. In conclusion, we show the crucial role of MADD in ATC tumorigenesis and metastasis and its potential implications as a molecular target for ATC therapy.
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http://dx.doi.org/10.1038/s41419-019-1351-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374448PMC
February 2019

Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis.

Semin Cancer Biol 2020 08 1;64:29-35. Epub 2019 Feb 1.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA. Electronic address:

Regulatory T-cells (Tregs) can facilitate immune evasion by tumor cells by dampening anti-tumor immunity. Reduced Teff/Treg ratio and enhanced Treg functional activity have been observed in patients suffering from different types of cancers, and attenuated Treg numbers/functions can serve as prognostic indicators. Normally, Tregs play an essential role in the maintenance of immune tolerance and prevention of autoimmunity. The most common immune checkpoint blockers (ICB) targeting co-inhibitory receptors such as anti-CTLA4 (ipilimumab and tremelimumab) and anti-PD1 (pembrolizumab and nivolumab)/anti-PD-L1 (atezolizumab) have achieved unprecedented success in cancer treatment by facilitating an effective anti-tumor immune response, at least in part, by blocking Treg mediated immunosuppression. While ICBs have shown remarkable success in cancer immunotherapy, immune-related adverse events (IRAEs) arising from ICB have forced consideration of ways to maintain immune homeostasis post ICB treatment. Preclinical models of IRAEs have shown a negative correlation between Treg numbers and IRAEs. Therefore, understanding the "ying-yang" role of Tregs in the regulation of autoimmunity and anti-tumor immunity is critical to provoking an effective anti-tumor response while maintaining immune homeostasis. Studies aimed at developing effective approaches to minimize IRAEs without compromising anti-tumor immunity are underway. Herein, we discuss 1) the critical role of key co-inhibitory receptors on Treg homeostasis and tumor tolerance; 2) how co-receptor blockade by cancer immunotherapy can lead to autoimmune adverse events; and 3) recently emerging management strategies to minimize autoimmune adverse events arising from ICB.
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http://dx.doi.org/10.1016/j.semcancer.2019.01.006DOI Listing
August 2020

Molecular aberrations and signaling cascades implicated in the pathogenesis of anaplastic thyroid cancer.

Biochim Biophys Acta Rev Cancer 2019 12 31;1872(2):188262. Epub 2018 Dec 31.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, United States; Jesse Brown VA Medical Center, Chicago, IL, United States. Electronic address:

Anaplastic Thyroid Cancer (ATC) accounts for >40% thyroid cancer-related deaths and has a dismal prognosis. In the past decade, significant efforts have been made towards understanding the pathogenesis of this disease and developing novel therapeutics. Unfortunately, effective treatment is still lacking and a more thorough understanding of ATC pathogenesis may provide new opportunities to improve ATC therapeutics. This review provides insights into ATC clinical presentation and pathology, and the putative role of genetic aberrations and alterations in molecular signaling pathways in ATC pathogenesis. We reviewed prevalent mutations, chromosomal abnormalities and fusions, epigenetic alterations and dysregulations in ATC, and highlighted several signaling cascades which appeared to be integral to ATC pathogenesis. Moreover, these features offer insights into de-differentiated, aggressive and drug-resistant phenotype of ATC, and thus may help in exploring potential new molecular targets for developing novel therapeutics.
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http://dx.doi.org/10.1016/j.bbcan.2018.12.003DOI Listing
December 2019

Vaccination With Mitoxantrone-Treated Primary Colon Cancer Cells Enhances Tumor-Infiltrating Lymphocytes and Clinical Responses in Colorectal Liver Metastases.

J Surg Res 2019 01 17;233:57-64. Epub 2018 Aug 17.

Division of Surgical Oncology, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois. Electronic address:

Background: Colorectal cancer remains a leading cause of cancer-related mortality worldwide. Metastases to the liver are often present at initial presentation and will form in most patients during their course of disease. We have previously demonstrated that enhanced trafficking and activation of tumor-infiltrating lymphocytes in colorectal liver metastases (CRLM) may improve antitumor immune responses. Thus, development of novel mechanisms to increase lymphocyte infiltration and activation are needed to improve patient outcomes.

Methods: CT26 murine colorectal cancer cells were treated with physiologic levels of the potent inducer of immunogenic cell death mitoxantrone (MTX). An in situ vaccine was created with treated cells in an established model of CRLM. Cells were evaluated by flow cytometry for cell cycle evaluation and calreticulin expression. Splenic and tumor-infiltrating lymphocytes were isolated for phenotypic studies.

Results: MTX-treatment of colon cancer cells resulted in a sub-G1 peak, inhibition of G1 cell cycle progression, and increased G2/M cell fractions while simultaneously increasing dynamic exposure of calreticulin on the cell surface (P < 0.05). Vaccination with MTX-treated cells resulted in significant decreases in CRLM formation associated with increased tumor-infiltrating leukocytes that displayed increased expression of the T cell surface activation marker CD69.

Conclusions: Vaccination with MTX-treated primary colon cancer cells enhances tumor-infiltrating lymphocytes and clinical responses in CRLM.
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http://dx.doi.org/10.1016/j.jss.2018.07.068DOI Listing
January 2019

Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells.

Cell Immunol 2019 05 29;339:41-49. Epub 2018 Sep 29.

Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA. Electronic address:

Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.
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http://dx.doi.org/10.1016/j.cellimm.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440877PMC
May 2019

Therapeutic advances in anaplastic thyroid cancer: a current perspective.

Mol Cancer 2018 10 23;17(1):154. Epub 2018 Oct 23.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.

Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.
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http://dx.doi.org/10.1186/s12943-018-0903-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198524PMC
October 2018

Identification of a Novel OX40L Dendritic Cell Subset That Selectively Expands Regulatory T cells.

Sci Rep 2018 10 8;8(1):14940. Epub 2018 Oct 8.

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

We have previously shown GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can induce the selective expansion of Tregs through the surface-bound molecule OX40L; however, the physiological role of this ex vivo derived DC subset remained to be elucidated. We determined GM-CSF administration to mice induced the generation of in vivo derived OX40L DCs, phenotypically similar to ex vivo OX40LG-BMDCs, in the spleen, brachial lymph nodes and liver. The generation of OX40L DCs correlated with increased percentages of functionally suppressive Tregs in the spleen, brachial lymph nodes, and liver of GM-CSF treated mice. DCs from GM-CSF treated mice expanded Tregs in CD4 T-cell co-cultures in an OX40L dependent manner, suggesting OX40L DCs may play a role in peripheral Treg homeostasis. Furthermore, comparing the transcriptome data of OX40L DCs to that of all immune cell types revealed OX40L DCs to be distinct from steady-state immune cells and, microarray analysis of OX40LG-BMDCs and OX40LG-BMDCs revealed higher expression of molecules that are associated with tolerogenic phenotype and could play important roles in the function of OX40L DCs. These findings suggest that OX40L DCs may represent a unique DC subset induced under inflammatory conditions that may play an essential role in maintaining Treg homeostasis.
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http://dx.doi.org/10.1038/s41598-018-33307-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175872PMC
October 2018

A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity.

J Autoimmun 2018 12 31;95:77-99. Epub 2018 Aug 31.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA; Department of Ophthalmology, Associate Dean for Technological Innovation and Training, University of Illinois College of Medicine, Room E-705, (M/C 790), 835 S. Wolcott Ave, Chicago, IL, 60612, USA. Electronic address:

The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
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http://dx.doi.org/10.1016/j.jaut.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289740PMC
December 2018

A single high-fat meal alters human soluble RAGE profiles and PBMC RAGE expression with no effect of prior aerobic exercise.

Physiol Rep 2018 07;6(14):e13811

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.

A high-fat diet can induce inflammation and metabolic diseases such as diabetes and atherosclerosis. The receptor for advanced glycation endproducts (RAGE) plays a critical role in metabolic disease pathophysiology and the soluble form of the receptor (sRAGE) can mitigate these effects. However, little is known about RAGE in the postprandial condition and the effect of exercise in this context. Thus, we aimed to determine the effects of a single high-fat meal (HFM) with and without prior exercise on peripheral blood mononuclear cell (PBMC) RAGE biology. Healthy males (n = 12) consumed a HFM on two occasions, one without prior exercise and one 16-18 hours following acute aerobic exercise. Total soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) were determined via ELISA and cleaved RAGE (cRAGE) was calculated as the difference between the two. Isolated PBMCs were analyzed for RAGE, ADAM10, TLR4, and MyD88 protein expression and ADAM10 activity. The HFM significantly (P < 0.01) attenuated sRAGE, esRAGE, and cRAGE by 9.7%, 6.9%, and 10.5%, respectively. Whereas, the HFM increased PBMC RAGE protein expression by 10.3% (P < 0.01), there was no meal effect on PBMC TLR4, MYD88, or ADAM10 protein expression, nor ADAM10 activity. There was also no exercise effect on any experimental outcomes. These findings suggest that PBMC RAGE and soluble RAGE may be important in the postprandial response to a HFM, and that prior aerobic exercise does not alter these processes in young healthy adult males. The mechanisms by which a HFM induces RAGE expression and reduces circulating soluble RAGE isoforms requires further study.
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http://dx.doi.org/10.14814/phy2.13811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060105PMC
July 2018

Implementing a STEMI system of care in urban Bangalore: Rationale and Study Design for heart rescue India.

Contemp Clin Trials Commun 2018 Jun 5;10:105-110. Epub 2018 Apr 5.

University of Illinois at Chicago Department of Emergency Medicine and Center for Global Health, 1940 Taylor M/C 584, Chicago, IL, USA.

Background: A system of care designed to measure and improve process measures such as symptom recognition, emergency response, and hospital care has the potential to reduce mortality and improve quality of life for patients with ST-elevation myocardial infarction (STEMI).

Objective: To document the methodology and rationale for the implementation and impact measurement of the Heart Rescue India project on STEMI morbidity and mortality in Bangalore, India.

Study Design: A hub and spoke STEMI system of care comprised of two interventional, hub hospitals and five spoke hospitals will build and deploy a dedicated emergency response and transport system covering a 10 Km. radius area of Bangalore, India. High risk patients will receive a dedicated emergency response number to call for symptoms of heart attack. A dedicated operations center will use geo-tracking strategies to optimize response times including first responder motor scooter transport, equipped with ECG machines to transmit ECG's for immediate interpretation and optimal triage. At the same time, a dedicated ambulance will be deployed for transport of appropriate STEMI patients to a hub hospital while non-STEMI patients will be transported to spoke hospitals. To enhance patient recognition and initiation of therapy, school children will be trained in basic CPR and signs and symptom of chest pain. Hub hospitals will refine their emergency department and cardiac catheterization laboratory protocols using continuous quality improvement techniques to minimize treatment delays. Prior to hospital discharge, secondary prevention measures will be initiated to enhance long-term patient outcomes.
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http://dx.doi.org/10.1016/j.conctc.2018.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047311PMC
June 2018

Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation.

Cell Mol Immunol 2019 02 26;16(2):138-153. Epub 2018 Mar 26.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.

Regulatory T cells (Tregs) play a pivotal role in immune-tolerance, and loss of Treg function can lead to the development of autoimmunity. Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery, where they suppress self-reactive effector T cells (Teff) responses. Recently, we showed that OX40L (TNFSF4) is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation (CAP-independent) in the presence of low-dose IL-2. Therefore, we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg (tTreg) development. Development of tTregs is a two-step process: Strong T-cell receptor (TCR) signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection, followed by a TCR-independent phase of tTreg development in which their maturation is driven by IL-2. Therefore, we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg development. OX40 mice had significantly reduced numbers of CD25Foxp3 tTreg precursors and CD25Foxp3 mature tTregs, while OX40L treatment of WT mice induced significant proliferation of these cell subsets. Relative to tTeff cells, OX40 was expressed at higher levels in both murine and human tTreg precursors and mature tTregs. In ex vivo cultures, OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs, which was mediated through the activation of AKT-mTOR signaling. These novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation, and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.
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http://dx.doi.org/10.1038/cmi.2018.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355936PMC
February 2019

Mitochondrial protein 18 (MTP18) plays a pro-apoptotic role in chemotherapy-induced gastric cancer cell apoptosis.

Oncotarget 2017 Aug 28;8(34):56582-56597. Epub 2017 Apr 28.

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

One of the severe limitations of chemotherapy is the development of drug resistance. However, the mechanisms underlying chemotherapy resistance remain to be elucidated. Mitochondrial mediated apoptosis is a form of cell death induced by chemotherapy. Several chemotherapeutic agents have been shown to induce mitochondrial fission, and finally activate the apoptosis cascade in various cancer cells. Here, we report that the mitochondrial membrane protein 18 (MTP18) induced mitochondrial fragmentation in gastric cancer cells under doxorubicin (DOX) exposure. Upon over-expression of MTP18, a sub-cytotoxic dose of DOX could sensitize a significant number of cells to undergo mitochondrial fission and subsequent apoptosis. These findings suggest that MTP18 can enhance the sensitivity of gastric cancer cells to DOX. Mechanistically, we found that MTP18 enriched dynamic-related protein 1 (DRP1) accumulation in mitochondria and it was responsible for mediating DOX-induced signaling required for mitochondrial fission. Intriguingly, MTP18 expression was downregulated during DOX treatment. Thus, down-regulation of MTP18 expression could be one of the resistance factors interfering with DOX-induced apoptosis in gastric cancer cells.
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http://dx.doi.org/10.18632/oncotarget.17508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593585PMC
August 2017

PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells.

Sci Rep 2017 07 26;7(1):6594. Epub 2017 Jul 26.

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3 Tregs, but not Foxp3 effector T-cells (Teff), when CD4 T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L/OX40 interaction has been shown to stimulate CD4 T-cells through the formation of a signalosome involving TRAF2/PKC-Ѳ leading to NF-kB activation. In this study, using CD4 T-cells from WT and OX40 mice we first established that OX40 mediated activation of NF-kB was critical for this Treg proliferation. Although CD4 T-cells from PKC-Ѳ mice were also defective in G-BMDC induced Treg proliferation ex vivo, this defect could be readily corrected by adding exogenous IL-2 to the co-cultures. Furthermore, by treating WT, OX40, and PKC-Ѳ mice with soluble OX40L we established that OX40L/OX40 interaction was required and sufficient to induce Treg proliferation in vivo independent of PKC-Ѳ status. Although PKC-Ѳ is dispensable for TCR-independent Treg proliferation per se, it is essential for optimum IL-2 production by Teff cells. Finally, our findings suggest that OX40L binding to OX40 likely results in recruitment of TRAF1 for downstream signalling.
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http://dx.doi.org/10.1038/s41598-017-05254-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529425PMC
July 2017

The epigenetic drug Trichostatin A ameliorates experimental autoimmune encephalomyelitis via T cell tolerance induction and impaired influx of T cells into the spinal cord.

Neurobiol Dis 2017 Dec 20;108:1-12. Epub 2017 Jul 20.

Dept. of Surgery, University of Illinois College of Medicine, Chicago, IL 60612, USA; Dept. of Microbiology & Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address:

Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Protection was accompanied by histone hyperacetylation, and reduced inflammation and axonal damage in the spinal cord. Drug treatment diminished the generation of CD4 memory T cells and induced tolerance in CD4 T cells recognizing the immunizing myelin peptide. During the early immunization period, CD4 T cells producing GM-CSF+IFN-γ, GM-CSF+IL-17A, as well as those expressing both IL-17A+IFN-γ (double-producers) were detected in the secondary lymphoid organs followed by the appearance of cells producing IFN-γ and GM-CSF. On the other hand, IFN-γ producing Th1 cells appear first in the spinal cord followed by cells producing IL-17A and GM-CSF. Treatment with Trichostatin A substantially reduced the frequencies of all T cells secreting various lymphokines both in the periphery and in the spinal cord. These data indicate that epigenetic modifications induced by histone hyperacetylation facilitates T cell tolerance induction in the periphery leading to reduced migration of T cells to the spinal cord and mitigation of neuronal damage and improved clinical outcome. These results suggest that epigenetic modulation of the genome may similarly offer benefits to multiple sclerosis patients via abrogating the function of encephalitogenic T lymphocytes without exerting severe side effects associated with currently used disease-modifying therapies.
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http://dx.doi.org/10.1016/j.nbd.2017.07.015DOI Listing
December 2017

Knockdown of Mtfp1 can minimize doxorubicin cardiotoxicity by inhibiting Dnm1l-mediated mitochondrial fission.

J Cell Mol Med 2017 Dec 23;21(12):3394-3404. Epub 2017 Jun 23.

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

The long-term usage of doxorubicin (DOX) is largely limited due to the development of severe cardiomyopathy. Many studies indicate that DOX-induced cardiac injury is related to reactive oxygen species generation and ultimate activation of apoptosis. The role of novel mitochondrial fission protein 1 (Mtfp1) in DOX-induced cardiotoxicity remains elusive. Here, we report the pro-mitochondrial fission and pro-apoptotic roles of Mtfp1 in DOX-induced cardiotoxicity. DOX up-regulates the Mtfp1 expression in HL-1 cardiac myocytes. Knockdown of Mtfp1 prevents cardiac myocyte from undergoing mitochondrial fission, and subsequently reduces the DOX-induced apoptosis by preventing dynamin 1-like (Dnm1l) accumulation in mitochondria. In contrast, when Mtfp1 is overexpressed, a suboptimal dose of DOX can induce a significant percentage of cells to undergo mitochondrial fission and apoptosis. These data suggest that knocking down of Mtfp1 can minimize the cardiomyocytes loss in DOX-induced cardiotoxicity. Thus, the regulation of Mtfp1 expression could be a novel therapeutic approach in chemotherapy-induced cardiotoxicity.
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http://dx.doi.org/10.1111/jcmm.13250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706585PMC
December 2017

LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases.

Cancer Res 2017 04 1;77(8):1880-1891. Epub 2017 Mar 1.

Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, Illinois.

The majority of patients with colon cancer will develop advanced disease, with the liver being the most common site of metastatic disease. Patients with increased numbers of tumor-infiltrating lymphocytes in primary colon tumors and liver metastases have improved outcomes. However, the molecular factors that could empower antitumor immune responses in this setting remain to be elucidated. We reported that the immunostimulatory cytokine LIGHT (TNFSF14) in the microenvironment of colon cancer metastases associates with improved patient survival, and here we demonstrate in an immunocompetent murine model that colon tumors expressing LIGHT stimulate lymphocyte proliferation and tumor cell-specific antitumor immune responses. In this model, increasing LIGHT expression in the microenvironment of either primary tumors or liver metastases triggered regression of established tumors and slowed the growth of liver metastases, driven by cytotoxic T-lymphocyte-mediated antitumor immunity. These responses corresponded with significant increases in tumor-infiltrating lymphocytes and increased expression of lymphocyte-homing signals in the metastatic tumors. Furthermore, we demonstrated evidence of durable tumor-specific antitumor immunity. In conclusion, increasing LIGHT expression increased T-cell proliferation, activation, and infiltration, resulting in enhanced tumor-specific immune-mediated tumor regressions in primary tumors and colorectal liver metastases. Mechanisms to increase LIGHT in the colon cancer microenvironment warrant further investigation and hold promise as an immunotherapeutic strategy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410174PMC
April 2017

Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death.

Cell Death Dis 2017 02 2;8(2):e2584. Epub 2017 Feb 2.

Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.

Immunotherapeutic approaches to manage patients with advanced gastrointestinal malignancies are desired; however, mechanisms to incite tumor-specific immune responses remain to be elucidated. Rose bengal (RB) is toxic at low concentrations to malignant cells and may induce damage-associated molecular patterns; therefore, we investigated its potential as an immunomodulator in colon cancer. Murine and human colon cancer lines were treated with RB (10% in saline/PV-10) for cell cycle, cell death, and apoptosis assays. Damage-associated molecular patterns were assessed with western blot, ELISA, and flow cytometry. In an immunocompetent murine model of colon cancer, we demonstrate that tumors regress upon RB treatment, and that RB induces cell death in colon cancer cells through G2/M growth arrest and predominantly necrosis. RB-treated colon cancer cells expressed distinct hallmarks of immunogenic cell death (ICD), including enhanced expression of calreticulin and heat-shock protein 90 on the cell surface, a decrease in intracellular ATP, and the release of HMGB1. To confirm the ICD phenotype, we vaccinated immunocompetent animals with syngeneic colon cancer cells treated with RB. RB-treated tumors served as a vaccine against subsequent challenge with the same CT26 colon cancer tumor cells, and vaccination with in vitro RB-treated cells resulted in slower tumor growth following inoculation with colon cancer cells, but not with syngeneic non-CT26 cancer cells, suggesting a specific antitumor immune response. In conclusion, RB serves as an inducer of ICD that contributes to enhanced specific antitumor immunity in colorectal cancer.
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http://dx.doi.org/10.1038/cddis.2016.473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386459PMC
February 2017

An Engineered Herpesvirus Activates Dendritic Cells and Induces Protective Immunity.

Sci Rep 2017 02 2;7:41461. Epub 2017 Feb 2.

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection. While attenuated HSV is explored for vaccine, the underlying event remains poorly defined. Here we report that recombinant HSV-1 with a mutation in the γ34.5 protein, a virulence factor, stimulates dendritic cell (DC) maturation which is dependent on TANK-binding kinase 1 (TBK1). When exposed to CD11 DCs, the mutant virus that lacks the amino terminus of γ34.5 undergoes temporal replication without production of infectious virus. Mechanistically, this leads to sequential phosphorylation of interferon regulatory factor 3 (IRF3) and p65/RelA. In correlation, DCs up-regulate the expression of co-stimulatory molecules and cytokines. However, selective inhibition of TBK1 precludes phosphorylation of IRF3 and subsequent DC activation by the γ34.5 mutant. Herein, the γ34.5 mutant is immune-stimulatory and non-destructive to DCs. Remarkably, upon immunization the γ34.5 mutant induces protection against lethal challenge by the wild type virus, indicative of its vaccine potential. Furthermore, CD11 DCs primed by the γ34.5 mutant in vivo mediate protection upon adoptive transfer. These results suggest that activation of TBK1 by engineered HSV is crucial for DC maturation, which may contribute to protective immunity.
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http://dx.doi.org/10.1038/srep41461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288694PMC
February 2017

Soluble OX40L and JAG1 Induce Selective Proliferation of Functional Regulatory T-Cells Independent of canonical TCR signaling.

Sci Rep 2017 01 3;7:39751. Epub 2017 Jan 3.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.

Regulatory T-cells (Tregs) play a pivotal role in maintaining peripheral tolerance. Increasing Treg numbers/functions has been shown to ameliorate autoimmune diseases. However, common Treg expansion approaches use T-Cell Receptor (TCR)-mediated stimulation which also causes proliferation of effector T-cells (Teff). To overcome this limitation, purified patient-specific Tregs are expanded ex vivo and transfused. Although promising, this approach is not suitable for routine clinical use. Therefore, an alternative approach to selectively expand functional Tregs in vivo is highly desired. We report a novel TCR-independent strategy for the selective proliferation of Foxp3+Tregs (without Teff proliferation), by co-culturing CD4+ T-cells with OX40 L+Jagged(JAG)-1+ bone marrow-derived DCs differentiated with GM-CSF or treating them with soluble OX40 L and JAG1 in the presence of exogenous IL-2. Tregs expanded using soluble OX40 L and JAG1 were of suppressive phenotype and delayed the onset of diabetes in NOD mice. Ligation of OX40 L and JAG1 with their cognate-receptors OX40 and Notch3, preferentially expressed on Tregs but not on Teff cells, was required for selective Treg proliferation. Soluble OX40L-JAG1-induced NF-κB activation as well as IL-2-induced STAT5 activation were essential for the proliferation of Tregs with sustained Foxp3 expression. Altogether, these findings demonstrate the utility of soluble OX40 L and JAG1 to induce TCR-independent Treg proliferation.
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http://dx.doi.org/10.1038/srep39751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206631PMC
January 2017

Targeting the metabolic pathway of human colon cancer overcomes resistance to TRAIL-induced apoptosis.

Cell Death Discov 2016 12;2:16067. Epub 2016 Sep 12.

Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA; Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, 835S. Wolcott Ave., MC790, Chicago, IL 60612, USA; The Creticos Cancer Center at Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA.

Colon cancer is a leading cause of cancer-related mortality for which targeted therapy is needed; however, trials using apoptosis-inducing ligand monotherapy to overcome resistance to apoptosis have not shown clinical responses. Since colon cancer cells selectively uptake and rapidly metabolize glucose, a property utilized for clinical staging, we investigated mechanisms to alter glucose metabolism in order to selectively target the cancer cells and to overcome evasion of apoptosis. We demonstrate TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance in the majority of human colon cancers tested and utilize the glucose analog 2-deoxy-d-glucose to sensitize TRAIL-resistant gastrointestinal adenocarcinoma cells, and not normal gastrointestinal epithelial cells, to TRAIL-induced apoptosis through enhanced death receptor 5 expression, downstream modulation of MAPK signaling and subsequent miRNA expression modulation by increasing the expression of miR-494 via MEK activation. Further, established human colon cancer xenografts treated with this strategy experience anti-tumor responses. These findings in colon adenocarcinoma support further investigation of manipulation of cellular energetics to selectively overcome resistance to apoptosis and to impart tumor regressions in established colon cancer tumors.
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http://dx.doi.org/10.1038/cddiscovery.2016.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018545PMC
September 2016

The mitochondrial ubiquitin ligase plays an anti-apoptotic role in cardiomyocytes by regulating mitochondrial fission.

J Cell Mol Med 2016 12 22;20(12):2278-2288. Epub 2016 Jul 22.

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Apoptosis plays a critical role in the development of myocardial infarction. Cardiomyocytes are enriched with mitochondria and excessive mitochondrial fission can trigger cellular apoptosis. Recently, the mitochondrial ubiquitin ligase (MITOL), localized in the mitochondrial outer membrane, was reported to play an important role in the regulation of mitochondrial dynamics and apoptosis. However, the underlying mechanism of its action remains uncertain. The present study was aimed at uncovering the role of MITOL in the regulation of cardiomyocyte apoptosis. Our results showed that MITOL expression was up-regulated in cardiomyocytes in response to apoptotic stimulation. Mitochondrial ubiquitin ligase overexpression blocked dynamin-related protein 1 accumulation in the mitochondria, and attenuated the mitochondrial fission induced by hydrogen peroxide. Conversely, MITOL knockdown sensitized cardiomyocytes to undergo mitochondrial fission, resulting in subsequent apoptosis. These findings suggest that MITOL plays a protective role against apoptosis in cardiomyocytes, and may serve as a potential therapeutic target for apoptosis-related cardiac diseases.
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http://dx.doi.org/10.1111/jcmm.12914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134389PMC
December 2016