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Amer A Beg, Jhanelle E Gray
No abstract text is available yet for this article.
August 2016: Epigenomics
Hong Zheng, Weipeng Zhao, Cihui Yan, Crystina C Watson, Michael Massengill, Mengyu Xie, Chris Massengill, David R Noyes, Gary V Martinez, Roha Afzal, Zhihua Chen, Xiubao Ren, Scott J Antonia, Eric B Haura, Brian Ruffell, Amer A Beg
PURPOSE: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ∼20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response. EXPERIMENTAL DESIGN: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response...
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Lu Chen, Brienne E Engel, Eric A Welsh, Sean J Yoder, Stephen G Brantley, Dung-Tsa Chen, Amer A Beg, Chunxia Cao, Frederic J Kaye, Eric B Haura, Matthew B Schabath, W Douglas Cress
INTRODUCTION: Serine/threonine kinase 11 gene (STK11), better known as liver kinase β1, is a tumor suppressor that is commonly mutated in lung adenocarcinoma (LUAD). Previous work has shown that mutational inactivation of the STK11 pathway may serve as a predictive biomarker for cancer treatments, including phenformin and cyclooxygenase-2 inhibition. Although immunohistochemical (IHC) staining and diagnostic sequencing are used to measure STK11 pathway disruption, there are serious limitations to these methods, thus emphasizing the importance of validating a clinically useful assay...
June 2016: Journal of Thoracic Oncology
Nishan Tchekmedyian, Jhanelle E Gray, Benjamin C Creelan, Alberto A Chiappori, Amer A Beg, Hatem Soliman, Bradford A Perez, Scott J Antonia
Immune checkpoint inhibitors produce durable long-term survival in some patients with advanced melanoma and lung cancer. Better immune targets and combination strategies can harness the immune system by supporting the three elements of a successful T-cell antitumor response: (A) generation of sufficient numbers of antitumor T cells within the lymphoid compartment; (B) effective T-cell trafficking and extravasation out of the lymphoid compartment, through the bloodstream, and into the tumor microenvironment; and (C) T-cell effector function within the tumor microenvironment that is characterized by the ability to bypass immune checkpoints, soluble and metabolic inhibitory factors, and inhibitory cells...
December 2015: Oncology (Williston Park, NY)
Eric B Haura, Amer A Beg, Uwe Rix, Scott Antonia
The activation state of an antitumor effector T cell in a tumor depends on the sum of all stimulatory signals and inhibitory signals that it receives in the tumor microenvironment. Accumulating data address the increasing complexity of these signals produced by a myriad of immune checkpoint molecules, cytokines, and metabolites. While reductionist experiments have identified key molecules and their importance in signaling, less clear is the integration of all these signals that allows T cells to guide their responses in health and in disease...
July 2015: Cancer Immunology Research
Nicholas T Woods, Alvaro N Monteiro, Zachary J Thompson, Ernest K Amankwah, Nina Naas, Eric B Haura, Amer A Beg, Matthew B Schabath
Biomarkers based on germline DNA variations could have translational implications by identifying prognostic factors and sub-classifying patients to tailored, patient-specific treatment. To investigate the association between germline variations in interleukin (IL) genes and lung cancer outcomes, we genotyped 251 single nucleotide polymorphisms (SNPs) from 33 different IL genes in 651 non-small cell lung cancer (NSCLC) patients. Analyses were performed to investigate overall survival, disease-free survival, and recurrence...
June 2015: Molecular Carcinogenesis
Crystina C Bronk, Sean Yoder, Emily L Hopewell, Shengyu Yang, Esteban Celis, Xue-Zhong Yu, Amer A Beg
In the accepted model of T-cell activation, parallel signal-transduction pathways activate the transcription factors NF-κB, NFAT, and AP-1 to drive clonal expansion of T cells in response to Ag. Genome-wide transcriptional profiling following Ag-induced CD8(+) T-cell activation in C57BL/6 mouse T cells revealed that genes regulated by NFAT were also reduced in the absence of NF-κB p50 and cRel subunits. Importantly, p50(-/-) cRel(-/-) CD8(+) T cells had significantly diminished NFAT and AP-1 activation compared with WT or PKCθ(-/-) CD8(+) T cells...
December 2014: European Journal of Immunology
Xingyu Wang, Junmei Wang, Hong Zheng, Mengyu Xie, Emily L Hopewell, Randy A Albrecht, Shoko Nogusa, Adolfo García-Sastre, Siddharth Balachandran, Amer A Beg
Host innate-immune responses are tailored by cell type to control and eradicate specific infectious agents. For example, an acute RNA virus infection can result in high-level expression of type 1 IFNs by both conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs), but whereas cDCs preferentially use RIG-I-like receptor (RLR) signaling to produce type 1 IFNs, pDCs predominantly use TLRs to induce these cytokines. We previously found that the IκB kinase β (IKKβ)/NF-κB pathway regulates early IFN-β expression, but not the magnitude of type 1 IFN expression following RLR engagement...
September 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Amer A Beg, Tahira Khan, Scott J Antonia
The activation of NFκB in the tumor microenvironment is associated with inflammatory responses that promote disease progression. We have recently found that the activation of NFκB in the tumor also regulates T cell-mediated immune responses, hence actively participating in cancer immunosurveillance. These findings call for reassessment of the function of NFκB within neoplastic lesions and open novel perspectives for anticancer immunotherapy.
October 1, 2013: Oncoimmunology
Jae-Young Kim, Amer A Beg, Eric B Haura
It is well known that non-canonical IκB kinases (IKK), IKKϵ and Tank-binding kinase 1 (TBK1), play a key role in anti-viral responses. Interestingly, they have recently emerged as novel survival kinases in several human cancers including lung cancer, given their roles in maintaining cancer cell survival and promoting oncogenic transformation. However, the molecular mechanisms by which IKKϵ/TBK1 are activated and IKKϵ/TBK1 mediate survival signal in cancer cells are still controversial. This article will briefly describe signaling pathways mediated by these non-canonical IKKs, especially focusing in lung cancer, and discuss their potential as molecular targets for lung cancer treatment...
October 2013: Expert Opinion on Therapeutic Targets
Kelley M K Haarberg, Jun Li, Jessica Heinrichs, Dapeng Wang, Chen Liu, Crystina C Bronk, Kane Kaosaard, Alexander M Owyang, Sacha Holland, Esteban Masuda, Kin Tso, Bruce R Blazar, Claudio Anasetti, Amer A Beg, Xue-Zhong Yu
Allogeneic hematopoietic cell transplantation (HCT) is the most effective therapy for hematopoietic malignancies through T-cell-mediated graft-vs-leukemia (GVL) effects but often leads to severe graft-vs-host disease (GVHD). Given that protein kinase Cθ (PKCθ), in cooperation with PKCα, is essential for T-cell signaling and function, we have evaluated PKCθ and PKCα as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKCα(-/-)/θ(-/-) donor T cells to induce GVHD was further reduced compared with PKCθ(-/-) T cells in relation with the relevance of both isoforms to allogeneic donor T-cell proliferation, cytokine production, and migration to GVHD target organs...
October 3, 2013: Blood
Matthew B Schabath, Anna R Giuliano, Zachary J Thompson, Ernest K Amankwah, Jhanelle E Gray, David A Fenstermacher, Kristen A Jonathan, Amer A Beg, Eric B Haura
Presently, there are few validated biomarkers that can predict survival or treatment response for non-small cell lung cancer (NSCLC) and most are based on tumor markers. Biomarkers based on germ line DNA variations represent a valuable complementary strategy, which could have translational implications by subclassifying patients to tailored, patient-specific treatment. We analyzed single nucleotide polymorphisms (SNPs) in 53 inflammation-related genes among 651 NSCLC patients. Multivariable Cox proportional hazard models, adjusted for lung cancer prognostic factors, were used to assess the association of genotypes and haplotypes with overall survival...
November 2013: Carcinogenesis
Jae-Young Kim, Eric A Welsh, Umut Oguz, Bin Fang, Yun Bai, Fumi Kinose, Crystina Bronk, Lily L Remsing Rix, Amer A Beg, Uwe Rix, Steven A Eschrich, John M Koomen, Eric B Haura
TANK-binding kinase 1 (TBK1) has emerged as a novel therapeutic target for unspecified subset of lung cancers. TBK1 reportedly mediates prosurvival signaling by activating NF-κB and AKT. However, we observed that TBK1 knockdown also decreased viability of cells expressing constitutively active NF-κB and interferon regulatory factor 3. Basal phospho-AKT level was not reduced after TBK1 knockdown in TBK1-sensitive lung cancer cells, implicating that TBK1 mediates unknown survival mechanisms. To gain better insight into TBK1 survival signaling, we searched for altered phosphoproteins using mass spectrometry following RNAi-mediated TBK1 knockdown...
July 23, 2013: Proceedings of the National Academy of Sciences of the United States of America
Yu Yu, Dapeng Wang, Kane Kaosaard, Chen Liu, Jianing Fu, Kelley Haarberg, Claudio Anasetti, Amer A Beg, Xue-Zhong Yu
Transcription factors of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and graft-versus-host disease (GVHD) remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute GVHD after allogeneic bone marrow transplantation using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel(-/-) T cells had a reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients...
September 2013: European Journal of Immunology
Emily L Hopewell, Weipeng Zhao, William J Fulp, Crystina C Bronk, Alexis S Lopez, Michael Massengill, Scott Antonia, Esteban Celis, Eric B Haura, Steven A Enkemann, Dung-Tsa Chen, Amer A Beg
NF-κB is constitutively activated in many cancer types and is a potential key mediator of tumor-associated inflammation, tumor growth, and metastasis. We investigated the role of cancer cell NF-κB activity in T cell-mediated antitumor responses. In tumors rendered immunogenic by model antigen expression or following administration of antitumor vaccines, we found that high NF-κB activity leads to tumor rejection and/or growth suppression in mice. Using a global RNA expression microarray, we demonstrated that NF-κB enhanced expression of several T cell chemokines, including Ccl2, and decreased CCL2 expression was associated with enhanced tumor growth in a mouse lung cancer model...
June 2013: Journal of Clinical Investigation
Crystina C Bronk, Xue-Zhong Yu, Amer A Beg
Protein kinase C isoform θ (PKCθ) is a key modulator of TCR signaling and mediates activation of NF-κB, NF-AT, and AP-1 transcription factors. Although in vitro studies of PKCθ(-/-) T cells have shown impaired activation responses, in vivo studies indicate that PKCθ requirement is not universal. While PKCθ is important in induction of experimentally induced autoimmune diseases in mice and generation of Th2 responses, it is not essential for induction of T cell proliferative and cytotoxic responses against influenza virus, LCMV, and vaccinia virus...
2012: Frontiers in Immunology
Emily L Hopewell, Crystina C Bronk, Michael Massengill, Robert W Engelman, Amer A Beg
Microbial adjuvants in vaccines activate key transcription factors, including NF-κB and interferon response factors (IRFs). However, the individual role of these transcription factor pathways in promoting adaptive immunity by adjuvants is not clear. It is widely believed that induction of a strong inflammatory response potentiates an adaptive immune response. In this study, we sought to determine whether activation of the pro-inflammatory inhibitor of κB kinase β (IKKβ) canonical NF-κB pathway promoted vaccine-induced immune responses...
March 2012: European Journal of Immunology
Siddharth Balachandran, Amer A Beg
No abstract text is available yet for this article.
October 2011: PLoS Pathogens
Qingguo Ruan, Vasumathi Kameswaran, Yan Zhang, Shijun Zheng, Jing Sun, Junmei Wang, Jennifer DeVirgiliis, Hsiou-Chi Liou, Amer A Beg, Youhai H Chen
The Th17 cells use the retinoid-related orphan receptor-γ (Rorg or Rorc) to specify their differentiation and lineage-specific function. However, how Rorg is switched on during Th17 differentiation is unknown. We report here that c-Rel and RelA/p65 transcription factors drive Th17 differentiation by binding to and activating two distinct Rorg promoters that control RORγT and RORγ expression, respectively. Similar to RORγT, RORγ is selectively expressed in Th17 cells and is effective in specifying the Th17 phenotype...
October 24, 2011: Journal of Experimental Medicine
Claudio Mauro, Shi Chi Leow, Elena Anso, Sonia Rocha, Anil K Thotakura, Laura Tornatore, Marta Moretti, Enrico De Smaele, Amer A Beg, Vinay Tergaonkar, Navdeep S Chandel, Guido Franzoso
Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration...
August 28, 2011: Nature Cell Biology
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