مجال
التميز
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تميز دراسي وبحثي + جوائز تفوقية
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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IFNγ-Dependent Interactions between ICAM-1 and LFA-1
Counteract Prostaglandin E2-Mediated Inhibition of Antitumor CTL Responses
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رابط إلى البحث:
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Click here
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تاريخ النشر:
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29/02/2016
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موجز عن البحث:
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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.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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British Association for cancer research
(Tumour microenvironment)- Basic Science to Noval Therapies
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تاريخ الإنعقاد:
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03/07/2013
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مكان
الإنعقاد:
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Bristol, UK
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طبيعة المشاركة:
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Paper and poster presentation
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عنوان المشاركة:
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ICAM-1- Mediated Regulation of Tumour +
Specific CD8 T cell responses in vivo
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ملخص المشاركة:
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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.
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المؤتمر (2):
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عنوان المؤتمر:
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British Society for immunology Congress
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تاريخ الإنعقاد:
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01/12/2014
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مكان
الإنعقاد:
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Brighton, UK
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طبيعة المشاركة:
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Paper presentation in the tumour microenvironment
and bright sparks competition
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عنوان المشاركة:
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Disabling adenosine-mediated suppression
of tumour-specific cytotoxic T lymphocyte function
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ملخص المشاركة:
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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
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المؤتمر (3):
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عنوان المؤتمر:
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British Society for immunology
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تاريخ الإنعقاد:
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02/12/2013
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مكان
الإنعقاد:
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Liverpool, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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ICAM-1- Mediated Regulation of Tumour Specific CD8+
T cell responses
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ملخص المشاركة:
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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.
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المؤتمر (4):
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عنوان المؤتمر:
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8th
Saudi Students’ Conference
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تاريخ الإنعقاد:
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31/01/2015
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مكان
الإنعقاد:
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London, UK
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طبيعة المشاركة:
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Paper presentation
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عنوان المشاركة:
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Disabling PGE2- mediated suppression on cytotoxic T
lymphocytes
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ملخص المشاركة:
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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.
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المؤتمر (5):
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عنوان المؤتمر:
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9th Saudi
Students’ Conference
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تاريخ الإنعقاد:
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13/02/2016
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مكان
الإنعقاد:
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Birmingham,
UK
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طبيعة المشاركة:
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Paper presentation
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عنوان المشاركة:
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Tumour Specific CD8+ T cells in a PGE2 Tumour
Microenvironment: What Does It Take to Wake Them Up?
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ملخص المشاركة:
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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.
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جوائز التكريم:
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الجائزة (1):
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مسمى الجائزة:
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Certificate of
Excellence Best Paper : Medicine and Medical Sciences
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الجهة المانحة:
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9th Saudi Students’ Conference Committee
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تاريخ منح الجائزة:
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13 – 14 /02/ 2016
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مجال التكريم:
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Best Paper in
Medicine and Medical Sciences
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