Molecular Genetics & Microbiology

Ellen Beswick

Ellen J. Beswick, Ph.D.

Molecular Genetics and Microbiology
MSC08 4660
1 University of New Mexico
Albuquerque, NM 87131-0001
E-mail: EBeswick@salud.unm.edu

Office: MRF 132
Office Tel: (505) 272-3383
Lab: MRF 108
Lab Tel: (505) 272-8938

Keywords: Colorectal Cancer, Gastric Cancer, Chronic Inflammation, Treg, Th17, Inflammatory Bowel Disease, Helicobacter pylori

Research Interests: Chronic inflammation and gastrointestinal cancers, novel immunotherapeutics for gastrointestinal cancers, T cell immunology in the GI tract, Treg and Th17 differentiation and responses in GI cancers, Helicobacter pylori, Inflammatory Bowel Disease,

I.  Chronic Inflammation and Immunotherapy.  Chronic inflammation is recognized as a risk factor for carcinogenesis and plays an important role in gastrointestinal cancers. Tumorigenesis is clearly a complex interaction where the transformation of epithelial cells is fostered by the local immune response of the microenvironment. During GI infection and inflammation, epithelial cells and stromal cells such as subepithelial myofibroblasts release a battery of proinflammatory cytokines and growth factors. When these responses become chronic, increased epithelial cell proliferative signaling and inhibition of tumor suppressor pathways may occur creating an environment conducive to carcinogenesis. We are interested in the production, receptor expression, and signaling of proinflammatory cytokines such as granulocyte colony-stimulating factor (G-CSF), macrophage migration inhibitory factor (MIF), interlekin-6, and interleukin-8 (IL-8) in the GI tract and how they may contribute to tumor growth and epithelial to mesenchymal transition.  Our goal is to identify novel targets in the tumor microenvornement that could be targeted to inhibit damaging inflammation while promoting protective immune responses.

II.  Dysregulation of mucosal CD4+ T cell response during GI infection and Inflammation. The mucosal T cell response is impaired during H. pylori infection, which contributes to chronicity of infection and the resulting pathogenicity. The existing response is polarized toward a Th1 response, including the production of interferon-γ, which plays an important role in the inflammatory response. The local development of Th17 cells also contributes to inflammation seen during infection. Despite the Th1 and Th17 responses, activated CD4+ cells fail to clear infection and are generally impaired in proliferation. Our work illustrates that gastric epithelial cells can not only act as antigen presenting cells, activating naïve T cell proliferation, but also contribute to the activated T cell anergy/suppression via expression of co-inhibitory molecules during H. pylori infection. Additionally, we have identified a mechanism of local induction of T regulatory (Treg) cells from naïve T cells through the upregulation of the co-inhibitory molecule PD-L1 on the epithelium. We are investigating the role of the gastric epithelium and subepithelial myofibroblasts in the induction of the Treg phenotype, the balance of Treg/Th17, and the inhibition of the T cell response during H. pylori infection and inflammatory bowel disease.

Our long term research interests include identifying inflammatory biomarkers and therapeutic targets for gastrointestinal cancers.

Selected Publications:

Link to PubMed

Castillo, E.F., Ray, A.L., and E.J. Beswick. MK2: An unrecognized regulator of tumor-promoting macrophages in colorectal cancer?  Macrophage 2016, in press.

Johnson, P., Beswick, E.J., Chao, C., Powell, D.W., Hellmich, M.R., and I.V. Pinchuk.  Isolation of CD90+ fibroblasts/myofibroblasts from human frozen gastrointestinal specimens. J Vis Exp,  2016, 107.

Huynh, P.T., Beswick, E.J., Coronado, Y.A., Johnson, P., O’Connell, M.R., Watts, T., Singh, P, Qui, S., Morris, K., Powell, D.W., and I.V. Pinkuck.  CD90+ Stromal cells are the major source of IL-6 which supports cancer stem-like cells and inflammation in colorectal cancer.  Int J Cancer, 2016, 138:1971-1981.

Ray, A.L.*, Castillo, E.F.*, Morris, K.T., Nofchissey, R.A., Weston, L.L., Samedi, V.G., Hanson, J.A., Pinchuk, I.V., and E.J. Beswick.  Blockade of the MK2 pathway is protective in inflammation-associated colorectal cancer development. Int J Cancer, 2016, 138:770-775. * contributed equally.

Morris, K.T., Castillo, E.F., Weston, L.L., Nofchissey, R.A., Ray, A.L., Hanson, J.A., Samedi, Hudson, L.G. and E.J. Beswick.  Anti-G-CSF treatment induces protective immunity in mouse colon cancer by promoting protective NK cell, macrophage and T cell responses. Oncotarget. 2015, Jun 4 Epub.

Beswick EJ, Saada JI, Johnson JR, Humen M, House J, Dann SM, Qiu S, Powell DW, Reyes VE, and I.V. Pinchuk. TLR4 activation enhances PD-L1-mediated tolerogenic capacity of colonic CD90+ stromal cells. J Immunol. 2014, 193:2218-2229 PMCID: PMC4142442

Morris, K.T., Nofchissey, R.A., Pinchuk, I.V., and E.J. Beswick.  Chronic Macrophage Migration Inhibitory Factor Exposure Induces Mesenchymal Epithelial Transition and Promotes Gastric and Colon Cancers.  PloS One 2014, 9:98656-986.  PMCID: PMC4041794

Morris, K.T., Khan, H., Ahmad, A., Weston, L.L., Nofchissey, R.A., Pinchuk, I.V., and E.J. Beswick.  G-CSFR is over-expressed in human gastric and colon cancers and promotes carcinoma cell proliferation and migration Br J Cancer. 2014, 110:1211-1220 PMCID: PMC3950854

Lina, T.T., Pinchuk, I.V., House, J., Y. Yamaoka, Graham, D.Y., Beswick, E.J.*, and V.E. Reyes.  CagA-dependent downregulation of B7-H2 on gastric mucosa and inhibition of Th17 responses during H. pylori infection. J Immunol. 2013, 191:3838-3846. PMCID: PMC3801271 *Co-senior author

Pinchuk, I.V., Morris, K.T., Nofchissey, R.A., Earley, R.B, Wu, J.Y., Ma, T.Y., and E.J. Beswick.  Stromal Cells Induce Th17 during Helicobacter pylori Infection and in the Gastric Tumor Microenvironment.  PLoS ONE 2013; 8:53798-53809.  PMCID: PMC3554710.

Ihan, A., Pinchuk, I.V., and E.J. Beswick.  Inflammation, Immunology, and Vaccines for Helicobacter pylori Infection. Helicobacter 2012; 17:16-21.  PMCID: PMC353541.

Beswick, E.J., Pinchuk, I.V., Earley, R.B., Schmitt, D.A., and V.E. Reyes.  The Role of Gastric Epithelial Cell-Derived TGF-{beta} in Reduced CD4+ T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection.  Infect Immun 2011; 79: 2737-45.  PMCID: PMC3191950.

Pinchuk, I.V., Beswick, E.J., Saada, J.I., Boya, G., Schmitt, D.A., Raju, G.S., Brenmoehl, J., Rogler, G., Reyes, V.E., and D.W. Powell.  Human colonic myofobroblasts promote the expansion of CD4+CD25highFoxP3+ regulatory T cells. Gastroenterology. 2011 140:  2019-30.  PMCID: PMC3109194.