Mary L Disis

University of Washington Seattle, Seattle, Washington, United States

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Publications (199)1042.02 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic mice were followed longitudinally from birth, and MPA-DMBA-treated mice from the time of carcinogen administration, for the development of mammary tumors. Tumor-infiltrating CD4(+) and CD8(+) T-cells, FOXP3(+) T-regulatory cells, and myeloid-derived suppressor cells were assessed by flow cytometry. Serum cytokines were evaluated in subsets of mice. Fine needle aspirates of tumors were collected and RNA was isolated to determine levels of immune and proliferation markers. Age of tumor onset and kinetics of tumor growth were significantly different among the models. Mammary tumors from TgMMTV-neu contained a lower CD8/CD4 ratio than that of other models (p < 0.05). MPA-DMBA-induced tumors contained a higher percentage of FOXP3(+) CD4(+) T-cells (p < 0.01) and MDSC (p < 0.001) compared with the other models. Individuals with significantly slower tumor growth demonstrated higher levels of Type I serum cytokines prior to the development of lesions compared to those with rapid tumor growth. Moreover, the tumors of animals with more rapid tumor growth demonstrated a significant increase in the expression of genes associated with Type II immunity than those with slower-progressing tumors. These data provide a foundation for the development of in vivo models to explore the relationship between endogenous immunity and response to standard therapies for breast cancer.
    Breast Cancer Research and Treatment 11/2014; · 4.47 Impact Factor
  • JAMA. 09/2014;
  • Mary L. Disis
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    ABSTRACT: The immune system plays a vital role in regulating the growth of tumors. Some types of inflammatory responses can promote tumor growth, while a tumor-specific adaptive immune response can potentially control tumor growth. Malignancies have the ability to evade the immune system, and proliferate and metastasize. The goal of immunotherapy is to marshal the specificity and long-term memory of the adaptive immune response to achieve durable tumor regression and possible cure, although, to date, this has only been achieved in a small subset of patients. A variety of approaches to immunotherapy have been investigated. These include administration of exogenous cytokines or therapeutic vaccines to increase the frequency of tumor-specific T cells, adoptive transfer of tumor-specific immune effector cells, and, more recently, the application of a variety of immune checkpoint inhibitors and agonists of co-stimulatory receptors to overcome tumor-induced immune-suppressive mechanisms. Some approaches have been more successful than others for reasons that are now becoming apparent, and these observations have led to an exciting resurgence in clinical research to develop more effective immunotherapeutic strategies.
    Seminars in Oncology 09/2014; · 4.33 Impact Factor
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    ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer. Robust cellular immune responses are associated with excellent outcomes in MCC patients, but are typically absent. We determined the prevalence and reversibility of class I MHC (MHC-I) downregulation in MCC, a potentially reversible immune evasion mechanism. Cell surface MHC-I expression was assessed on 5 MCC cell lines using flow cytometry as well as immunohistochemically on tissue microarrays representing 114 patients. Three additional patients were included who had received intralesional interferon treatment and had evaluable before and after specimens. mRNA expression analysis of antigen presentation pathway genes from 35 MCC tumors was used to examine mechanisms of down-regulation. 84% of MCCs (n=114) demonstrated reduced MHC-I expression as compared to surrounding tissues and 51% had poor or undetectable expression. Expression of MHC-I was lower in polyomavirus-positive MCCs as compared to virus-negative MCCs (p<0.01). The MHC-I downregulation mechanism was multifactorial and did not depend solely on HLA gene expression. Treatment of MCC cell lines with ionizing radiation, etoposide, or interferon resulted in MHC-I upregulation, with interferons strongly upregulating MHC expression in vitro and in 3 of 3 patients treated with intralesional interferon. MCC tumors may be amenable to immunotherapy, but downregulation of MHC-I is frequently present in these tumors, particularly those that are polyomavirus-positive. This downregulation is reversible with any of several clinically available treatments that may thus promote the effectiveness of immune stimulating therapies for MCC.
    Cancer immunology research. 08/2014;
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    ABSTRACT: ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.
    Breast Cancer Research and Treatment 08/2014; · 4.47 Impact Factor
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    ABSTRACT: The use of autoantibodies for the early detection of breast cancer has generated much interest as antibodies can be readily assayed in serum when antigen levels are low. Ideally, diagnostic autoantibodies would be identified in individuals who harbored pre-invasive disease/high risk lesions leading to malignancy. Prospectively collected human serum samples from these individuals are rare and not often available for biomarker discovery. We questioned whether transgenic animals could be used to identify cancer-associated autoantibodies present at the earliest stages of the malignant transformation of breast cancer.
    Journal of translational medicine. 05/2014; 12(1):121.
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    ABSTRACT: Immunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4(+) T-helper (TH1) and CD8(+) cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor-binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN-γ and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-γ (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N-terminus epitope-specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naïve T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N-terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P < 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C-terminus with the N-terminus vaccine abrogated the antitumor response of the N-terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self-tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes. Cancer Res; 74(10); 1-9. ©2014 AACR.
    Cancer Research 04/2014; · 9.28 Impact Factor
  • Mary L. Disis
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    ABSTRACT: The immune system plays a vital role in regulating the growth of tumors. Some types of inflammatory responses can promote tumor growth, while a tumor-specific adaptive immune response can potentially control tumor growth. Malignancies have the ability to evade the immune system, and proliferate and metastasize. The goal of immunotherapy is to marshal the specificity and long-term memory of the adaptive immune response to achieve durable tumor regression and possible cure, although, to date, this has only been achieved in a small subset of patients. A variety of approaches to immunotherapy have been investigated. These include administration of exogenous cytokines or therapeutic vaccines to increase the frequency of tumor-specific T cells, adoptive transfer of tumor-specific immune effector cells, and, more recently, the application of a variety of immune checkpoint inhibitors and agonists of co-stimulatory receptors to overcome tumor-induced immune-suppressive mechanisms. Some approaches have been more successful than others for reasons that are now becoming apparent, and these observations have led to an exciting resurgence in clinical research to develop more effective immunotherapeutic strategies.
    Seminars in Oncology 09/2014; · 4.33 Impact Factor
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    ABSTRACT: Inflammasome activation has been shown to regulate both innate and adaptive immune responses. It is important to investigate whether immune-enhancing natural products can also activate inflammasome. The current study examined the potential of protein-bound polysaccharide-K (PSK), a hot water extract from Trametes versicolor, to activate inflammasome. Using THP-1 cells, we have demonstrated that PSK induces both pro-IL-1β and mature IL-1β in THP-1 cells in a caspase 1- and NLRP3-dependent manner. PSK also induces IL-1β and IL-18 in human PBMC. Cathepsin B is required for PSK-induced inflammasome activation as CA-074-Me, a cathepsin B inhibitor, significantly decreased PSK-induced IL-1β. PSK induces NLRP3 at both mRNA and protein level. Comparison of PSK-induced IL-1β in bone marrow-derived macrophages from wild type C57BL/6 mice, TLR2(-/-), P2X7R(-/-) and NLRP3(-/-) mice demonstrated that PSK-induced IL-1β is dependent on both TLR2 and NLRP3. P2X7R is not required for PSK-induced inflammasome activation, but enhances PSK-induced caspase-1 activation and IL-1β induction. Altogether, these results demonstrated that PSK induces inflammasome activation and production of IL-1β in a TLR2- and NLRP3-dependent mechanism. These results provide novel insights into the mechanisms of the immune modulatory effects of PSK.
    Innate Immunity 12/2013; · 2.68 Impact Factor
  • Mary L Disis, Sasha E Stanton
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    ABSTRACT: An effective immune response has the potential for breast cancer sterilization with marked reduction in the potential for disease relapse. Adaptive type I immune cells uniquely have the capability of (i) cytotoxic T-cell activation and proliferation until all antigen expressing cells are eradicated, (ii) traversing endothelial barriers to penetrate tumor deposits wherever they occur, and (iii) immunologic memory, which allows the persistence of destructive immunity over the years it may take for breast cancer micrometastases to become clinically evident. Numerous recent investigations suggest that some breast cancers stimulate the type of immunity that results in a decreased risk of relapse. Moreover, the endogenous type I tumor microenvironment or type I immunity induced by drugs or biologic agents may improve response to standard therapies, further lowering the probability of disease recurrence. Clin Cancer Res; 19(23); 6398-403. ©2013 AACR.
    Clinical Cancer Research 12/2013; 19(23):6398-403. · 7.84 Impact Factor
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    ABSTRACT: Effective elicitation of endogenous immunity is associated with improved prognosis for cancer patients. Clinical evidence in hematological and solid cancers shows that intratumoral injection of immunostimulatory genes primes and augments endogenous T cell responses. The ability of pro-inflammatory chemokines/cytokines to facilitate migration/activation of antigen-presenting cells (APC) and lymphocytes prompted our modeling of intratumoral delivery of a chemokine/cytokine combination for breast cancer treatment. Here, we demonstrate that expression of chemokine ligand 21 (CCL21) and interferon gamma (IFNγ) in tumors improves tumor specific T cell recruitment to tumor and activation in the tumor milieu. IFNγ and CCL21 were delivered into tumor cells via plasmids, and transfected cells were seeded to form spheroids on three-dimensional (3D) chitosan-alginate (CA) scaffolds. Co-expression of CCL21 and IFNγ, as evidenced by qRT-PCR and ELISA, induced increased recruitment, binding, and infiltration of anti-neu (p98) peptide specific T cells into the breast tumors as determined by SEM and immunofluorescence assays. The co-expression promoted recruitment of only p98 T cells, but not naïve T cells, demonstrating an antigen-restricted activation. Furthermore, the co-expression impacted T helper (Th) cell immunity, promoting an increase in secretion of pro-inflammatory Th-associated cytokine, tumor necrosis factor alpha (TNFα), and cytotoxic T lymphocyte (CTL)-associated protease, Granzyme B (GzB). Therefore, 3D CA scaffolds may be a useful breast cancer tumor microenvironment model to evaluate T cell function. Further characterization of CCL21-IFNγ mediated anti-tumor immunity will potentially benefit the development of chemokine/cytokine combination platforms as anti-cancer agents.
    Anti-cancer agents in medicinal chemistry 11/2013;
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    ABSTRACT: This phase I study evaluated the feasibility of expanding HER-2/neu (HER2) vaccine-primed peripheral blood T-cells ex vivo and assessed the safety of T-cell infusions. Eight patients with HER2(+) treatment refractory metastatic cancers were enrolled. T-cells could be expanded to predefined parameters in seven patients (88 %). Ninety-two percent of adverse events were grade 1 or 2. Three of seven patients developed infusion-related inflammatory reactions at their disease sites. HER2-specific T-cells significantly increased in vivo compared to pre-infusion levels (p = 0.010) and persisted in 4/6 patients (66 %) over 70 days after the first infusion. Partial clinical responses were observed in 43 % of patients. Levels of T-regulatory cells in peripheral blood prior to infusion (p < 0.001), the level of HER2-specific T-cells in vivo (p = 0.030), and development of diverse clonal T-cell populations (p < 0.001) were associated with response. The generation of HER2 vaccine-primed autologous T-cells for therapeutic infusion is feasible and well tolerated. This approach provides a foundation for the application of T-cell therapy to additional solid tumor types.
    Cancer Immunology and Immunotherapy 10/2013; · 3.64 Impact Factor
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    ABSTRACT: A multi-antigen multi-peptide vaccine, targeting proteins expressed in pre-invasive breast lesions, can stimulate Type I CD4+ T-cells which have been shown to be deficient in both breast cancer patients and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multi-antigen peptide vaccine specific for neu, IGFBP-2 and IGF-IR at a time when some of the animals already had pre-invasive lesions (18 weeks of age). While immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multi-antigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors which did arise. Protection was mediated by CD4+ T-cells and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8+ T-cells as compared to controls (p=0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. While the combination of lapatinib and vaccination performed similarly to vaccination alone (p=0.735), bexarotene and vaccination significantly enhanced disease free survival (p<0.0001) and approximately 90% of mice showed no pathologic evidence of carcinomas at 1 year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemo-immunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease.
    Cancer Prevention Research 10/2013; · 4.89 Impact Factor
  • Mary L Disis, Karolina Palucka
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    ABSTRACT: There have been significant advances in the development and application of novel therapeutic approaches and improved diagnostics for cancer in the past decade. Manipulation and/or assessment of cancer-specific immunity have been central to these advances. Murine models are a standard for the preclinical development of cancer immunotherapeutics. However, critical advances in our understanding of the role of the immune microenvironment and the assessment of cancer-specific immunity have not been fully applied to rodent models. Methods to preserve the function of immune cells after cryopreservation and standard approaches to quantitative immune assays have not been developed. Furthermore, a detailed evaluation of the immune tumor environment, which can impact a clinical response to different agents, is rarely undertaken as models are being contemplated. Rapid translation of immunoncology agents to the clinic will require standardization of immunologic assay methods and a more detailed immunologic characterization of common mouse models. Outlined here are the critical elements in assessing immunity in cancer mouse models and suggestions concerning the standardization of approaches when using these models for the study of immunoncology.
    Cold Spring Harbor Protocols 09/2013; · 4.63 Impact Factor
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    ABSTRACT: The University of Washington (UW) Institute for Translational Health Sciences (ITHS), funded by a Clinical and Translational Sciences Award program, has supplemented its initial Kellogg Logic Model-based program evaluation with the eight judgment-based evaluative elements of the World Health Organization's (WHO) Health Services Assessment Model. This article describes the relationship between the two models, the rationale for the decision to supplement the evaluation with WHO evaluative elements, the value-added results of the WHO evaluative elements, and plans for further developing the WHO assessments.
    Evaluation &amp the Health Professions 09/2013; · 1.48 Impact Factor
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    ABSTRACT: Immunoprevention refers to a strategy of preventing pathogen-associated and spontaneous cancers through the use of vaccines, antibodies, and immune modulators. Immune modulators function by enhancing the endogenous ability of the immune system to monitor for malignancy, so-called "immunosurveillance." There is growing evidence that many of the most promising cancer chemoprevention agents including aspirin, COX-2 inhibitors, aromatase inhibitors, and bisphosphonates mediate their effects, in part, by enhancing immunosurveillance and reversing the immune evasive mechanisms that premalignant lesions use. In the following review, we introduce critical components of the human immune surveillance system-dendritic cells, T cells, and immune suppressive cells-and discuss the emerging data suggesting that common chemoprevention agents may modulate the function of these immunologic cells. Cancer Prev Res; 6(8); 764-73. ©2013 AACR.
    Cancer Prevention Research 08/2013; 6(8):764-73. · 4.89 Impact Factor
  • John B Liao, Mary L Disis
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    ABSTRACT: While therapeutic vaccines for ovarian cancer represent only a small fraction of active clinical trials, growing interest in this area and the accumulated data supporting the use of vaccines in cancer treatment, portend further expansion of trials incorporating these strategies. This review explores the rationale for the use of vaccines for the treatment of ovarian cancer. It examines vaccine platforms that have been investigated and reviews the data from these studies. We also highlight recently reported phase 2 and 3 clinical trials with clinical outcomes as endpoints. Finally, we consider directions for the next generation of vaccines in light of these findings and our emerging understanding of agents that may augment vaccine responses by targeting the immunosuppressive impact of the tumor microenvironment.
    Gynecologic Oncology 06/2013; · 3.93 Impact Factor
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    ABSTRACT: Numerous lines of evidence demonstrate that breast cancer is immunogenic; yet, there are few biologically relevant immune targets under investigation restricting the exploration of vaccines to limited breast cancer subtypes. Insulin-like growth factor-I receptor (IGF-IR) is a promising vaccine candidate since it is overexpressed in most breast cancer subtypes, is part of a dominant cancer growth pathway, and has been validated as a therapeutic target. We questioned whether IGF-IR was immunogenic in cancer patients. IGF-IR-specific IgG antibodies were significantly elevated in early-stage breast cancer patients at the time of diagnosis as compared to volunteer donors (p = 0.04). Predicted T-helper epitopes, derived from the IGF-IR extracellular and transmembrane domains, elicited a significantly higher incidence of Th2 immunity in breast cancer patients as compared to controls (p = 0.01). Moreover, the magnitude of Th2 immunity was greater in breast cancer patients compared to controls (p = 0.02). In contrast, both breast cancer patients and volunteer donors demonstrated a similar incidence of Th1 immunity to IGF-IR domains with the predominant response directed against epitopes in the intracellular domain of the protein. As the incidence of IGF-IR type I immunity was not associated with a breast cancer diagnosis, we questioned whether other factors were contributing to the presence of IGF-IR-specific T-cells in both populations. While age was not associated with Th1 immunity, we observed a significantly greater magnitude of IGF-IR IFN-γ-secreting T-cells in obese subjects as compared to overweight (p < 0.001) or healthy-weight (p = 0.006) subjects, regardless of breast cancer diagnosis. No significant difference was observed for Th2 incidence or magnitude when stratified by age (p = 0.174, p = 0.966, respectively) or body mass index (p = 0.137, p = 0.174, respectively). Our data demonstrate that IGF-IR is a tumor antigen and IGF-IR-specific Th1 immunity may be associated with obesity rather than malignancy.
    Breast Cancer Research and Treatment 06/2013; · 4.47 Impact Factor
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    ABSTRACT: Polysaccharide K (PSK) is a widely used mushroom extract that has shown anti-tumor and immunomodulatory effects in both preclinical and clinical studies. Therefore, it is important to understand the mechanism of actions of PSK. We recently reported that PSK can activate toll-like receptor 2 and enhances the function of NK cells. The current study was undertaken to study the effect of PSK on gamma delta (γδ) T cells, another important arm of the innate immunity. In vitro experiments using mouse splenocytes showed that γδ T cells produce IFN-γ after treatment with PSK and have up-regulated expression of CD25, CD69, and CD107a. To investigate whether the effect of PSK on γδ T cells is direct or indirect, purified γδ T cells were cultured either alone or together with bone marrow-derived DC in a co-culture or trans-well system and then stimulated with PSK. Results showed that direct cell-to-cell contact between γδ T cells and DC is required for optimal activation of γδ T cells. There was also reciprocal activation of DC by PSK-activated γδ T cells, as demonstrated by higher expression of costimulatory molecules and enhanced production of IL-12 by DC in the presence of γδ T cells. PSK can also co-stimulate γδ T cells with anti-TCR and anti-CD3 stimulation, in the absence of DC. Finally, in vivo treatment with PSK activates γδ T cells among the tumor infiltrating lymphocytes, and depleting γδ T cells during PSK treatment attenuated the anti-tumor effect of PSK. All together, these results demonstrated that γδ T cells are activated by PSK and contribute to the anti-tumor effect of PSK.
    Cancer Immunology and Immunotherapy 05/2013; · 3.64 Impact Factor
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    ABSTRACT: The length of time required for pre-invasive adenoma (AD) to progress to carcinoma, the immunogenicity of colorectal cancer (CRC), and the identification of high risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible. We hypothesized that genes upregulated in AD relative to normal tissue, which maintained increased expression in CRC, would encode proteins suitable as putative targets for immunoprevention. We evaluated existing AD and CRC microarray datasets and identified 160 genes that were ≥ 2-fold up-regulated in both AD and CRC relative to normal colon tissue. We further identified 23 genes that demonstrated protein over-expression in colon AD and CRC based on literature review. Silencing the most highly up-regulated genes, CDH3, CLDN1, KRT23, and MMP7, in AD and CRC cell lines resulted in a significant decrease in viability (p<0.0001) and proliferation (p<0.0001) as compared to controls and an increase in cellular apoptosis (p<0.05 for CDH3, KRT23). Results were duplicated across cell lines representing microsatellite instability (MSI), CpG island methylator (CIMP) and chromosomal instability (CIN) phenotypes suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes. To determine whether these proteins were immunogens, we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 (p=0.006), KRT23 (p=0.0007), and MMP7 (p<0.0001) serum IgG in cases as compared to controls. These data demonstrate a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified 3 candidates suitable for vaccine development.
    Cancer Prevention Research 05/2013; · 4.89 Impact Factor

Publication Stats

8k Citations
1,042.02 Total Impact Points

Institutions

  • 1994–2014
    • University of Washington Seattle
      • • Center for Translational Medicine in Women's Health
      • • Department of Materials Science and Engineering
      • • Division of Pulmonary and Critical Care Medicine
      • • Division of Oncology
      • • Department of Medicine
      Seattle, Washington, United States
  • 2013
    • Bastyr University
      Kenmore, Washington, United States
  • 2011
    • Providence Portland Medical Center
      Portland, Oregon, United States
  • 2009–2011
    • University of Pittsburgh
      • • School of Medicine
      • • Division of Hematology/Oncology
      Pittsburgh, PA, United States
    • The University of Tokyo
      • Institute of Medical Science
      Tokyo, Tokyo-to, Japan
  • 2008–2010
    • Mayo Clinic - Rochester
      • Department of Oncology
      Rochester, MN, United States
    • Korea University
      • Department of Internal Medicine
      Seoul, Seoul, South Korea
  • 2005–2008
    • Mayo Foundation for Medical Education and Research
      • Department of Immunology
      Scottsdale, AZ, United States
    • Becton, Dickinson and Company (BD)
      • BD Biosciences
      Franklin Lakes, NJ, United States
  • 2000–2006
    • Fred Hutchinson Cancer Research Center
      • Division of Public Health Sciences
      Seattle, Washington, United States
    • Johannes Gutenberg-Universität Mainz
      • III. Department of Medicine
      Mainz, Rhineland-Palatinate, Germany
  • 2004
    • Columbia University
      • Department of Surgery
      New York City, NY, United States
  • 2003
    • University of Wisconsin, Madison
      • Department of Medicine
      Madison, MS, United States
  • 2002
    • Technische Universität München
      München, Bavaria, Germany
  • 1999
    • Saint Vincent Hospital
      Worcester, Massachusetts, United States