فاطمه سالم حسن باسنقاب

 


      
 
الاسم الاول: 
فاطمه
اسم العائلة: 
باسنقاب
الدرجة العلمية: 
دكتوراة
مجال الدراسة: 
الطب والخدمات الصحية
المؤسسة التعليمية: 
Bristol University

مجال التميز

تميز دراسي وبحثي + جوائز تفوقية

 

 

البحوث المنشورة

 

البحث (1):

 

عنوان البحث:

IFNγ-Dependent Interactions between ICAM-1 and LFA-1 Counteract Prostaglandin E2-Mediated Inhibition of Antitumor CTL Responses

رابط إلى البحث:

Click here

تاريخ النشر:

29/02/2016

موجز عن البحث:

 

Tumor-expressed ICAM-1 interaction with LFA-1 on naïve tumor-specific CD8+T cells not only stabilizes adhesion, but, in the absence of classical B7-mediated costimulation, is also able to provide potent alternative costimulatory signaling resulting in the production of antitumor cytotoxic T lymphocyte (CTL) responses. This study shows that overproduction of prostaglandin (PG) E2by metastatic murine renal carcinoma (Renca) cells inhibited direct priming of tumor-specific CTL responsesin vivoby preventing the IFNγ-dependent upregulation of ICAM-1 that is vital during the initial priming of naïve CD8+T cells. The addition of exogenous IFNγ during naïve CD8+T-cell priming abrogated PGE2-mediated suppression, and overexpression of ICAM-1 by tumor cells restored IFNγ production and proliferation among PGE2-treated tumor-specific CD8+T cells; preventing tumor growthin vivo These findings suggest that novel anticancer immunotherapies, which increase expression of ICAM-1 on tumor cells, could help alleviate PGE2-mediated immunosuppression of antitumor CTL responses.Cancer Immunol Res; 4(5); 1-12. ©2016 AACR.

 

 

المؤتمرات العلمية:

 

 

 

المؤتمر (1):

 

عنوان المؤتمر:

British Association for cancer research (Tumour microenvironment)- Basic Science to Noval Therapies

تاريخ الإنعقاد:

03/07/2013

مكان الإنعقاد:

Bristol, UK

طبيعة المشاركة:

Paper  and poster presentation

عنوان المشاركة:

ICAM-1- Mediated Regulation of Tumour + Specific CD8 T cell responses in vivo

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ملخص المشاركة:

 

Priming of naive CD8+ T-cells by tumour antigens to become an effector Cytotoxic T-Lymphocytes (CTL), can occur either as a consequence of direct or indirect antigen presentation by metastatic tumour cells or dendritic cells respectively. However, despite the activation of large numbers of tumour specific CTL their subsequent inability to control tumour growth often results from the immune suppression that is created within the tumour microenvironment. Several mechanisms of tumour mediated immune suppression have been shown which can vary from one tumour to another. Elevated levels of prostaglandin (PG) E2 secretion within tumours can directly suppress anti-tumour CTL responses through the increased level of intracellular cyclic Adenosine monophosphate (cAMP) within CD8+ T-cells which in turn reduces T-cell proliferation as well as IFN-γ production and prevents the up regulation of ICAM-1. Experiments in this project are aimed to investigate the role of ICAM-1 in generating CTL in PGE2 tumour microenvironment. At least two signals are required for direct prime of naive CD8+ T-cells by tumours; the first comes from the cognate interaction between T-cell receptor with antigen presented by MHC class I molecules on antigen presenting cells. The second, a classical co-stimulatory signal, is provided by the binding of T cell expressed CD28 on tumour cells. In the absence of classical stimulation (CD28 and CD80/CD86), ICAM-1 provides an alternative costimulatory signal via the binding to LFA-1 expressed by naïve CD8+ T-cells. We have shown that cyclooxygenase (COX-2) over expression in tumour cells (T3 cells) results in an increased level of PGE2. T3 tumour- bearing BALB/c mice lose their CTL effector function in vivo and are able to metastasis to TDLN. Significantly, our data shows that over expression of ICAM-1 on tumour cells can counteract the immune suppressive effect of PGE2 by restoring the productive activation of CTL. However, the addition of exogenous soluble ICAM-1 does not show a strong effect as the bound ICAM-1. In addition, ICAM-1 over expression on cancer cells stops the tumour growth in vivo.

 

 

المؤتمر (2):

 

عنوان المؤتمر:

British Society for immunology Congress

تاريخ الإنعقاد:

01/12/2014

مكان الإنعقاد:

Brighton, UK

طبيعة المشاركة:

Paper  presentation in the tumour microenvironment and bright sparks competition

عنوان المشاركة:

Disabling adenosine-mediated suppression of tumour-specific cytotoxic T lymphocyte function

 

 

 

 

 

 

 

 

 

 

 

 

 

ملخص المشاركة:

 

Cancer cells are able to shape their microenvironment promoting both tumour cell proliferation as well as immune suppression. Understanding mechanisms of tumour-mediated immune suppression will enable the development of effective immunotherapies to combat cancer. One such mechanism occurs due to elevated concentrations of adenosine, which are shown to regulate the immune response and prevent tissue damage. Adenosine is generated by the extracellular conversion of ATP by the ectoenzymes CD39 and CD73. We have shown that the loss of tumour-specific CD8+ cytotoxic T Lymphocyte (CTL) function that occurs after tumour-infiltration is associated with the presence of huge numbers of regulatory Foxp3+ , CD25+ , CD4+ tumourinfiltrating lymphocytes (TIL), compared with the tumour draining lymph nodes, where priming of tumour-specific effector CTL occurs. Significantly, more than 90% of these Foxp3+ , CD25+ , CD4+ TIL cells express both CD39 and CD73. We have shown that Adenosine exerts it's negative effect on tumour-specific CTL responses by the binding to the A2A and A2B adenosine receptors, which in turn reduces both CD8+ T cell proliferation and anti-tumour CTL effector function in vitro and in vivo. Our data indicate that disabling adenosine-mediated immune-suppression could significantly enhance the efficacy of immunotherapeutic protocols that rely upon vaccination or the direct transfer of tumour-specific CD8+ T cells to control tumour growth. 3

 

 

المؤتمر (3):

 

عنوان المؤتمر:

British Society for immunology

تاريخ الإنعقاد:

02/12/2013

مكان الإنعقاد:

Liverpool, UK

طبيعة المشاركة:

Poster presentation

عنوان المشاركة:

ICAM-1- Mediated Regulation of Tumour Specific CD8+ T cell responses

 

 

 

 

 

 

 

 

 

 

 

 

ملخص المشاركة:

 

Introduction Tumour infiltrating CD8+ T cell are essential in controlling and preventing tumour growth. Priming naive CD8+ T cells by tumour antigens to become effector Cytotoxic T-Lymphocytes (CTL), occurs either as a consequence of direct or indirect antigen presentation by metastatic tumour cells or dendritic cells respectively. However, despite the activation of large numbers of tumour specific CTL their subsequent inability to control tumour growth often results from the immune suppression that is created within the tumour microenvironment. Several mechanisms of tumour-mediated immune suppression have been shown which can vary from one tumour to another. We have shown that elevated levels of prostaglandin (PG) E2 secretion within tumours can directly suppress anti-tumour CTL responses through the increased level of intracellular cyclic Adenosine monophosphate (cAMP) within CD8+ T cells, which in turn, reduces T cell proliferation as well as IFN-γ production and prevents the up regulation of ICAM-1. ICAM-1 provides potent alternative co-stimulatory signal via the binding to LFA-1 expressed by naïve CD8+ T cells that is crucial for CD8+ T cell activation in the absence of the classical stimulation (CD80/CD86) on most cancer cells. Material and Methods Murine renal carcinoma cells (Renca) which over-express cyclooxygenase 2, resulting in increased levels of PGE2 production, were further transfected with a recombinant plasmid containing full length murine ICAM-1. Using Renca specific TcR transgenic CD8+ T cell, experiments were carried out to assess the anti-tumour CTL response to these Renca cells in vitro and in vivo. Results ICAM-1 is a potent alternative costimulatory molecule for naïve CD8+ T cell activation. Overexpression of ICAM-1 by Renca cells can counteract the immune suppressive effect that PGE2 has on CD8+ T cell responses in vitro and can restore productive activation of CTL responses in vivo which can prevent tumour growth. Conclusion Immunotherapeutic strategies that target ICAM-1 interactions with LFA-1 on tumour-specific CD8+ T cells could counteract tumour mediated immune-suppression and control tumour growth.

 

 

المؤتمر (4):

 

عنوان المؤتمر:

8th Saudi Students’ Conference

تاريخ الإنعقاد:

31/01/2015

مكان الإنعقاد:

London, UK

طبيعة المشاركة:

Paper presentation

عنوان المشاركة:

Disabling PGE2- mediated suppression on cytotoxic T lymphocytes

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ملخص المشاركة:

 

It is generally believed that the immune system can be modified to combat tumour cells particular metastases and minimal residual disease (MRD) that can remain after standard treatments have been employed. CD8+ T-cells can recognize tumour antigen in two ways; direct and indirect antigen presentation by tumour cells or dendritic cells respectively to become an effector Cytotoxic T-Lymphocytes (CTL) resulting in tumour regression. However, the tumour microenvironment can directly suppress anti-tumour CTL responses. Many immune suppression mechanisms have been identified which are known to vary from one tumour to another, occur simultaneously and at different stages in tumour growth. As such, simply targeting one of these circuits may, at best, partially alleviate the suppression; and that this may or may not restore immunity sufficiently enough to control tumour growth. What is more likely is that immunotherapy must be a multi-targeted process to ensure that sufficient immunity is restored. Therefore, developing effective immunotherapeutic strategies to combat tumour growth and progression will not only rely upon gaining a detailed understanding of the mechanisms of priming naive tumour-specific CD8+ T-cells to become effective CTL, but also a detailed understanding of the many factors that influence CTL function within the tumour microenvironment. At least two signals are required to prime CTL; the first comes from the interaction between T-cell receptor (TcR) with Antigen (Ag) presented by MHCI on antigen presenting cells (APC). The second signal which is known as classical co stimulatory signal is provided by the binding of CD28 and CD80/ CD86 on CD8+T-cells and tumour cells respectively. However, usually classical costimulation does not provided by most cancer cells and therefore interaction between naïve CD8+ T-cells and tumour cells often leads to tolerance induction. It has been shown that in the absence of classical stimulation, ICAM-1 can provide an alternative co-stimulatory signal 2 via the binding to LFA-1 expressed by naïve CD8+ T-cells. Thus, the lack of CTL priming occurs as a result of PGE2 binding to receptors on naïve T-cells which in turn increase intracellular cAMP resulting in reducing T-cell proliferation and IFN- γ production and prevents the up regulation of ICAM-1, leading to the absence of co-stimulatory signals. The data described in this report suggest that over-expression of ICAM-1 can counteract the immunosuppressive action of prostaglandin (PG) E2 upon tumour-specific CTL unlike the additional exogenous soluble ICAM-1 which has no impact in CTL response.

 

 

المؤتمر (5):

 

عنوان المؤتمر:

9th Saudi Students’ Conference

تاريخ الإنعقاد:

13/02/2016

مكان الإنعقاد:

Birmingham, UK

طبيعة المشاركة:

Paper presentation

عنوان المشاركة:

Tumour Specific CD8+ T cells in a PGE2 Tumour Microenvironment: What Does It Take to Wake Them Up?

 

 

 

 

 

 

 

 

ملخص المشاركة:

 

Tumour infiltrating cytotoxic T lymphocytes (CTLs) play powerful roles in tumour killing, however, cancers adopt many strategies to induce immunosuppression. Effective priming of naive CD8+ T cells to become CTLs occurs via the cognate interactions of TcR with tumour peptide on MHC-I, and CD28 with CD80/CD86, on T cells and APCs respectively. Here we report the absence of CD80/CD86 by Renal carcinomas (Renca). The expression of ICAM-1 provides a potent alternative co-stimulation to KdHA-specific CL4 CD8+ T cells derive them to produce IFN-γ which is crucial for the upregulation of ICAM-1 on tumour cells. We have shown that cyclooxygenase (COX-2) overexpression by tumour cells (Renca-T3) results in an increased level of prostaglandin (PG) E2. PGE2 in tumours can directly inhibit anti-tumour CTLs. Renca-T3-bearing mice lose their CTL function in vivo and metastasize to the TDLNs. Significantly, our data show that overexpression of ICAM-1 on Renca-T3 cells can counteract the immune suppressive effect of PGE2 by restoring the productive activation of CL4 CTLs.

 

 

جوائز التكريم:

 

الجائزة (1):

 

 

مسمى الجائزة:

 

Certificate of Excellence Best Paper : Medicine and Medical Sciences

 

 

الجهة المانحة:

9th Saudi Students’ Conference Committee

 

تاريخ منح الجائزة:

13 - 14 /02/ 2016

مجال التكريم:

 

Best Paper in Medicine and Medical Sciences

المرفقالحجم
BACR Certificate 2013.pdf‏165.23 ك.بايت
BSI 2013 poster participation.pdf‏107.58 ك.بايت
BSI 2014 Oral participation.pdf‏72.79 ك.بايت
SSC8 _participation_CERTificate.pdf‏272.07 ك.بايت
SSCUK9_best paper_certificate.pdf‏236.56 ك.بايت