Definition of the T Cell-Mediated Immune Response to Mammaglobin, a Novel Breast Cancer-Associated Protein PDF Download
Are you looking for read ebook online? Search for your book and save it on your Kindle device, PC, phones or tablets. Download Definition of the T Cell-Mediated Immune Response to Mammaglobin, a Novel Breast Cancer-Associated Protein PDF full book. Access full book title Definition of the T Cell-Mediated Immune Response to Mammaglobin, a Novel Breast Cancer-Associated Protein by . Download full books in PDF and EPUB format.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
Get Book Here
Book Description
The elucidation of the immune response to cancer should be of great help in the development of new therapeutic strategies for the treatment of breast cancer. Based on recent advances in our understanding of antigen recognition by T lymphocytes, it has been possible to identify several tumor-associated antigens (TAA) recognized by CTLs. However, the expression for these TAAs has been shown to be relatively low in breast cancer tumor cells. A new protein named mammaglobin has been demonstrated to be exclusively expressed in the mammary epithelium. In addition, 90% of primary breast cancer tumors have high levels of expression of the mammaglobin protein. Given the exclusive mammaglobin expression in breast cancer tumors, this novel protein may prove to be a TAA highly specific for breast cancer that could be utilized in the near future for in vitro breast cancer-specific activation of CTLs. The discovery of mammaglobin-derived antigenic peptides that are highly expressed in breast cancer tumor tissue and are recognized by CTLs offer many exciting future therapeutic options for the treatment of breast cancer.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
Get Book Here
Book Description
The elucidation of the immune response to cancer should be of great help in the development of new therapeutic strategies for the treatment of breast cancer. Based on recent advances in our understanding of antigen recognition by T lymphocytes, it has been possible to identify several tumor-associated antigens (TAA) recognized by CTLs. However, the expression for these TAAs has been shown to be relatively low in breast cancer tumor cells. A new protein named mammaglobin has been demonstrated to be exclusively expressed in the mammary epithelium. In addition, 90% of primary breast cancer tumors have high levels of expression of the mammaglobin protein. Given the exclusive mammaglobin expression in breast cancer tumors, this novel protein may prove to be a TAA highly specific for breast cancer that could be utilized in the near future for in vitro breast cancer-specific activation of CTLs. The discovery of mammaglobin-derived antigenic peptides that are highly expressed in breast cancer tumor tissue and are recognized by CTLs offer many exciting future therapeutic options for the treatment of breast cancer.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
Get Book Here
Book Description
Overexpression of Her-2/neu is one of the major alterations in breast cancer and is associated with metastatic disease, poor prognosis and overall survival. Her-2/neu is a self antigen, therefore, self-tolerance is a major burden for the induction of effective antitumor immune responses. Clinical trials show that immunizations with neu-antigens do not promote a potent protective mediated immune response. In order to develop a therapy to target Her-2/neu expressing tumors, we have devised a strategy where we can endow T cells with antitumor specificity and bypass the effect of self-tolerance. We developed an approach by genetic engineering where we have genetically altered T cell populations to express high affinity T cell receptors (TCR) chains specific for Her-2/neu. High affinity TCR were obtained from A2.1 transgenic mice immunized with A2. 1 -Her-2/neu immunodominant epitopes. The TCR genes from the CTLs were cloned and engineered to be expressed on T cells. T cells expressing these engineered TCR can recognize and kill Her-2/neu expressing breast tumors. These results demonstrate a novel strategy to target Her-2/neu positive tumors for the treatment of breast cancer.
Author: Yeni Romero
Publisher:
ISBN:
Category :
Languages : en
Pages :
Get Book Here
Book Description
Tumors consist of a diverse population of cancer cells as well as various tumor-infiltrating immune cells, soluble factors, and extracellular matrix proteins, which are collectively known as the tumor immune microenvironment (TIME). The interactions between cancer cells and their microenvironment heavily influence tumor progression and therapeutic responses, often leading to tumor immune evasion and therapeutic resistance. Understanding these complex interactions will help develop novel strategies to target tumor cells or improve the efficacy of existing therapies. The goal of my research was to explore the role of two regulators of the tumor immune microenvironment, PD-L1 and regulatory T cells, in triple negative breast cancer (TNBC). Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune system that acts as a "brake" to keep the body's immune responses under control. However, in cancer, PD-L1 expression leads to immune evasion and poor disease outcomes. In breast cancer, PD-L1 expression is most upregulated in the TNBC subtype. Under certain circumstances, transmembrane PD-L1 can be cleaved, generating a soluble form containing an intact receptor-binding domain. In my research, I investigated the cleavage of PD-L1 expressed on the surface of tumor cells. I found that a ~37-kDa N-terminal cleavage product of PD-L1 is released to the culture media. Analysis of the ~18-kDa C-terminal PD-L1 fragment demonstrated that this fragment is unstable and readily eliminated by lysosomal degradation. Furthermore, I identified ADAM10 and ADAM17, two members of the cell surface family of ADAM metalloproteases, as mediators of the cleavage of transmembrane PD-L1. Regulatory T cells (Tregs) are a subset of T cells that play a role in regulating or suppressing other immune cells. Tregs regulate the immune response to self and foreign antigens and help prevent autoimmune diseases by maintaining immune homeostasis. In cancer, Tregs are involved in tumor development and progression by inhibiting effector cells and reducing anti-tumor immunity. In TNBC, infiltration of Tregs into the TIME is often associated with resistance to anti-PD-L1 therapy and poor patient survival. Therefore, a better understanding of the mechanisms regulating the numbers of Tregs in the TIME of TNBC is necessary to tackle the problem of immunotherapy resistance. Claudin-low breast tumors are known to have increased numbers of tumor-infiltrating lymphocytes, specifically Tregs, as well as upregulated expression levels of ADAM12, an active ADAM metalloprotease. My goal was to investigate the role of ADAM12 in T cell accumulation to the tumor microenvironment in vivo using a mouse transplantation model of claudin-low breast cancer. Specifically, I investigated the accumulation of Tregs and other T cell subsets to tumors with or without expression of ADAM12. I found that the frequency of Tregs in tumor immune infiltrates was increased in tumors that lacked ADAM12 expression. Collectively, these findings give insight into the complex regulatory roles that PD-L1 and Tregs play in the breast cancer TIME.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
Get Book Here
Book Description
The provision of the T cell costimulatory molecule B7 to tumor cells can be an effective means of triggering a tumor specific cytolytic T cells response. One way to provide B7 to tumor cells would be to couple an anti-tumor antibody either directly to B7 or to an antibody to the B7 counterreceptor on T cells, CD28. To this end, a fusion protein has been developed which incorporates a single chain antibody fragment (scFv) to erbB-2 (Her2/neu), an oncogene product overexpressed by 30-50% of breast carcinomas, and the extracellular domain of B7.2 (CD86). This fusion protein was expressed and purified from Pichia pastoris, shown to retain binding activity to both counter receptors, erbB-2 and CD28, and shown to provide the costimulatory signal to T cells through CD28. Thus, our fusion protein was shown capable of targeting erbB-2 postive tumor cells and delivering a CD28 specific T cell costimulatory signal. Further studies should characterize the fusion protein in erbB-2 tumor bearing mice for in vivo tumor targeting, biodistribution, and efficacy.
Author: Michele Martin
Publisher:
ISBN:
Category :
Languages : en
Pages : 356
Get Book Here
Book Description
In the era of personalized cancer treatment, adoptive T cell therapy (ACT) shows promise for the treatment of solid cancers. However, partial or mixed responses remain common clinical outcomes due to the heterogeneity of tumours. Indeed, in many patients it is typical to see a response to ACT in one tumour nodule, while others show little or no response. Thus, defining the tumour features that distinguish those that respond to ACT from those that do not would be a significant advance, allowing clinicians to identify patients that might benefit from this treatment approach. The first chapter of this thesis provides the necessary background to understand the principals behind and components of ACT. This chapter also offers selected historical advances contributing to the current state of the field. The second chapter introduces a novel murine model of breast cancer developed to investigate the tumour-specific mechanisms associated with immune evasion in an ACT setting. The third chapter describes the in vivo characterization of mammary tumour cell lines derived from our mouse model that reliably showed complete, partial or no response to ACT. Using these cell lines, we were able to characterize in vivo tumour-specific differences in cytotoxic T cell trafficking, infiltration, activation, and proliferation associated with response to ACT. In the fourth chapter, we used bioinformatics approaches to develop a preliminary predictive gene signature associated with response to ACT in our mammary tumour model. We used this signature to predict outcome and then test a number of murine mammary tumours in vivo, with promising results, wherein 50% of tumours responded to ACT as predicted based upon gene expression. Thus, using an innovative model for breast cancer, these results suggest that there are tumour-specific features that can be used a priori to predict how a tumour will respond to adoptive T cell therapy. Importantly, these findings might facilitate the design of immunotherapy trials for human breast cancer.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 23
Get Book Here
Book Description
The anti-apoptotic protein Bcl-2 is overexpressed in a majority of breast cancers, and is associated with a diminished apoptotic response and resistance to various anti-tumor agents. Bcl-2 inhibition is currently being explored as a possible strategy for sensitizing breast cancer cells to standard chemotherapeutic agents. Antisense (AS) Bcl-2 oligonucleotides represent one method for blocking the anti-apoptotic effects of Bcl-2. In this study we demonstrate that AS Bcl-2 efficiently blocks Bcl-2 expression, resulting in apoptosis of breast cancer cells. AS Bcl-2-mediated cytotoxicity was associated with induction of the B-cell translocation gene 1 (BTG1). Importantly, knockdown of BTG1 reduced AS Bcl-2-mediated cytotoxicity in breast cancer cells. Further, BTG1 expression appears to be negatively regulated by Bcl-2, and exogenous expression of BTG1 induced apoptosis. These results suggest that BTG1 is a Bcl-2-regulated mediator of apoptosis in breast cancer cells, and that its induction contributes to AS Bcl-2-mediated cytotoxic effects.
Author: Michele Martin
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
Get Book Here
Book Description
In the era of personalized cancer treatment, adoptive T cell therapy (ACT) shows promise for the treatment of solid cancers. However, partial or mixed responses remain common clinical outcomes due to the heterogeneity of tumours. Indeed, in many patients it is typical to see a response to ACT in one tumour nodule, while others show little or no response. Thus, defining the tumour features that distinguish those that respond to ACT from those that do not would be a significant advance, allowing clinicians to identify patients that might benefit from this treatment approach. The first chapter of this thesis provides the necessary background to understand the principals behind and components of ACT. This chapter also offers selected historical advances contributing to the current state of the field. The second chapter introduces a novel murine model of breast cancer developed to investigate the tumour-specific mechanisms associated with immune evasion in an ACT setting. The third chapter describes the in vivo characterization of mammary tumour cell lines derived from our mouse model that reliably showed complete, partial or no response to ACT. Using these cell lines, we were able to characterize in vivo tumour-specific differences in cytotoxic T cell trafficking, infiltration, activation, and proliferation associated with response to ACT. In the fourth chapter, we used bioinformatics approaches to develop a preliminary predictive gene signature associated with response to ACT in our mammary tumour model. We used this signature to predict outcome and then test a number of murine mammary tumours in vivo, with promising results, wherein 50% of tumours responded to ACT as predicted based upon gene expression. Thus, using an innovative model for breast cancer, these results suggest that there are tumour-specific features that can be used a priori to predict how a tumour will respond to adoptive T cell therapy. Importantly, these findings might facilitate the design of immunotherapy trials for human breast cancer.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 8
Get Book Here
Book Description
In the Her-2/neu model of spontaneous breast cancer development it is clear that the immune system of these transgenic mice are tolerant to the neu protein (1-3). In this model not only does the overexpression of neu lead to tumorogenesis but the neu protein is the target of both humoral and cellular immunity which prevent tumor-induced death in the non-transgenic mice (1, 4). Indeed, while immunity to neu can be demonstrated in the neu-transgenic mice (partial breaking of tolerance), this immunity is inadequate in terms of preventing the spontaneous development of tumors and preventing death from tumor challenge. We have demonstrated in vitro that the PKC inhibitor Go6976 has the ability to selectively inhibit TCR induced tolerance induction while only minimally inhibiting T cell activation. We hypothesize that the addition of Go6976 to vaccine protocols will inhibit the reinduction of neu specific tolerance and thus facilitate immune mediated protection against the development of spontaneous breast cancer development and tumor challenge.
Author: Eric J. Bieber
Publisher: Cambridge University Press
ISBN: 1107040396
Category : Medical
Languages : en
Pages : 1127
Get Book Here
Book Description
Written with the busy practice in mind, this book delivers clinically focused, evidence-based gynecology guidance in a quick-reference format. It explores etiology, screening, tests, diagnosis, and treatment for a full range of gynecologic health issues. The coverage includes the full range of gynecologic malignancies, reproductive endocrinology and infertility, infectious diseases, urogynecologic problems, gynecologic concerns in children and adolescents, and surgical interventions including minimally invasive surgical procedures. Information is easy to find and absorb owing to the extensive use of full-color diagrams, algorithms, and illustrations. The new edition has been expanded to include aspects of gynecology important in international and resource-poor settings.
Author: Runjan Chetty
Publisher: Cambridge University Press
ISBN: 1316592065
Category : Medical
Languages : en
Pages : 525
Get Book Here
Book Description
Providing a unique A-Z guide to antibodies for immunohistology, this is an indispensable source for pathologists to ensure the correct application of immunohistochemistry in daily practice. Each entry includes commercial sources, clones, descriptions of stained proteins/epitopes, the full staining spectrum of normal and tumor tissues, staining pattern and cellular localization, the range of conditions of immunoreactivity, and pitfalls of the antibody's immunoprofile, giving pathologists a truly thorough quick-reference guide to sources, preparation and applications of specific antibodies. Appendices provide useful quick-reference tables of antibody panels for differential diagnoses, as well as summaries of diagnostic applications. Expanded from previous editions with over forty new entries, this handbook for diagnostic, therapeutic, prognostic and research applications of antibodies is an essential desktop book for practicing pathologists as well as researchers, residents and trainees.
