Download 1 Expression of immune inhibitory ligands and

Expression of immune inhibitory ligands and enzymes in pancreatic adenocarcinoma
Backround. Pancreatic cancer is the 5th leading cause of cancer related death in the developed
world and more than 260,000 people die of the disease every year worldwide[1]. Due to its aggressive
nature and late presentation long term survival is uncommon with 5-year survival at 6%. Only 15-20%
of patients are candidates for surgical tumor resection with the 5-year survival in these patients
improving to 22%. Traditional chemotherapy is minimally effective. Thus different therapeutic
strategies against pancreatic cancer are needed.
Recently, increased attention has been focused on the role of the immune system in the
development and progression of pancreatic cancer [2]. It is known that the tumor microenvironment is
rich in immune inhibitory ligands, enzymes and cytokines that suppress the immune system and
inhibit immune effector cells [2]. Some of these molecules, such as PD-L1, have already been
themselves successful targets of therapy in melanoma and lung cancer and clinical trials in many other
cancers are underway[3-5]. Other immune inhibitory molecules such as the galectin Gal-9, HVEM and
HLA-G have shown promise as future therapeutic targets or as biomarkers in many cancers[6-9].
Moreover, the enzymes involved in tryptophan metabolism, IDO and TDO, as well as their catabolic
product kynurenine, which can be detected in serum, have also been found to be potential biomarkers
in various cancers[10] and drugs targeting IDO are in clinical development. Tryptophan is vital for the
survival of immune infiltrating effector cells in the tumor microenvironment, while kynurenine
suppresses T-cell functions, and cancer cells that express IDO and/or TDO convert tryptophan to its
metabolites, thereby limiting immune cell anti-tumor activity.
However, these immune inhibitory ligands and enzymes have hardly been studied in pancreatic
cancer. IDO expression has been examined in a small study of 17 patients with pancreatic cancer [11],
while PD-L1 has been investigated in 2 studies of 40 and 51 patients, respectively, showing that its
expression is associated with poor prognosis [12, 13]. Expression of the other ligands and enzymes in
pancreatic cancer has not been performed. In addition, there are no studies in any cancer yet testing the
expression of multiple of these molecules in a single cohort, and as a result the interaction between
them in unknown.
Objectives
1. Characterize the expression and co-expression of the immune inhibitory molecules PD-L1, Gal-9,
IDO, TDO, HVEM, and HLA-G in a cohort of patients with resected pancreatic adenocarcinoma.
2. Characterize the presence of CD8+ effector T-cells, NK cells and the immunosuppressive Foxp3+
Tregs in the same patients and in particular in relation to the presence or absence of the above
immune inhibitory molecules.
3. Based on the tissue and blood expression of immune inhibitory ligands in pancreatic cancer
hypothesize on rational immunotherapeutic combination therapies that may be further tested in
pre-clinical or clinical trials.
Methods and techniques used in this project:
1. Patient identification and retrieval of clinical information from the electronic medical record
system: List of patients who have undergone pancreatic cancer resection at our institution is
available (around 1,500 patients). From these 250 patients will be chosen for inclusion in the
study.
2. Tissue Microarray (TMA) construction: Our group has experience with TMA construction [1416]. We construct TMAs using an automated instrument (Beacher™) which significantly cuts time
and effort needed with the traditional semi-automatic or manual techniques.
3. Immunohistochemistry (the antibodies for the project are already available in our laboratory).
4. ELISA
We are looking for an enthusiastic Medical, Biology, Life Sciences (or equivalent) Master student who
is highly motivated to do laboratory work and participate in scientific discussions. The steps of this
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project are well defined and no new techniques need to be developed. The project is expected to be
completed within 4-5 months from the start date and the student is expected to be proficient with TMA
construction and manipulation (including cutting), immunohistochemistry and ELISA.
For further information, please contact:
Jaap Kwekkeboom, PhD; [email protected]
Kostandinos Sideras, MD; [email protected]
Laboratory of Gastroenterology and Hepatology, Erasmus MC
www.gastrolab.nl
Refferences
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Sideras, K., et al., Role of the immune system in pancreatic cancer progression and
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Wang, Y., et al., Expression of HLA-G in patients with hepatocellular carcinoma.
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Witkiewicz, A., et al., Expression of indoleamine 2,3-dioxygenase in metastatic
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