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Neurosurgery Department

Main focus

Our lab studies the unique immunology of brain tumors combining basic-science with clinically-applied investigation.
The brain is a unique immune organ that is regarded as 'immunologically privileged', i.e. the immune system monitors it less-stringently than it does other organs. Utilizing the discrepancy between the immune surveillance inside and outside the brain, the lab has developed a novel method to treat brain tumors utilizing a concept we termed 'Split Immunity'.




Current Research topics

  1. Development of scientific and clinical insights into the concept of 'Split Immunity'. The concept is soon to be translated from bench to bedside.
  2. Mapping of the entire adaptive and innate cellular immune milieu found inside human brain tumors using advanced multicolor (up to 8-color) flow cytometry.
  3. Using an approach termed "immune cytomics" that uses systems-biology and a wet-immunology, to study the network of intra-tumoral cellular interactions. Such interactions are formed between the different subsets of immune cells, and between immune cells and tumor cells.
  4. Development of a high-throughput proteomic- genomic-immunologic approach to identify  the immunodominant tumor associated antigens recognized by tumor infiltrating T cells.
  5. Identification of systems-level predictive and prognostic markers for detection of effective anti-tumor responses in glioma patients.




Research Tools/Services

In-vivo work

 Animal models for brain tumors:

We use stereotactic injections to inoculate rats and mice with several different types of syngeneic ('autologous') brain tumors. These brain tumor models are highly aggressive and closely resemble brain tumors found in humans.  Additionally we have developed a rat glioma cell-line that expresses luciferase. This cell-line enables the in-vivo monitoring of the quantity of living cells that grow inside a rat's brain, using the IVIS system.

In-vitro/ex-vivo work

Tumor enzymatic dissociation to single cells:

We developed a method to enzymatically dissociate human and animal brain tumors to single cells with very high viability (>90%). Working with ex-vivo produced cells of high viability reduces the frequent in-vitro artifacts caused by the excessive death of cells dissociated by other methods.


Advanced flow cytometry:

We developed several different flow-cytometric antibody panels to identify all prominent immune cells found inside a brain tumor . Using these carefully designed multicolor (~8 color) panels we can currently identify all tumor infiltrating and tumor resident immune cells found within human brain tumors, including: CTL, Helper T cells, NK cells, NKT cells (2 subsets), macrophages (M1/M2), plasmacytoid dendritic cells, myeloid dendritic cells (3 subtypes),neutrophils, eosinophils, and microglia (2 activation states). The correct identification of these cells enables their purification via sorting. Purified cells are then used in order to run subsequent high-resolution genomic or proteomic assays.

 

Functional ex-vivo assays:  

 Short (1-3d) ex-vivo assays are done on freshly isolated tumor and peripheral blood leukocytes. Such assays may uncover subtle immune responses on the single cell-level of either peripheral immune cells or intratumoral immune cells.
We use these functional flow cytometric panels to follow immune functional markers such as: TNF-alpha, TGF-beta, IFN-gamma, Interleukins (e.g. IL2, IL13), CD107a (cytotoxicity/degranulation marker), PD1 (T-cell activation/exhaustion marker), proliferation (CFSE), and cellular viability (via amine dyes). Each of the constructed T-cell functional panels also follows T-cell identity (using  CD3/4/8/(DUMP: CD14- 19- 20- Viability) ) and four of the functional markers listed  above.
In addition to T-cell functional panels we have also constructed several panels to functionally monitor human dendritic cells. These panels follow the activation and maturation state of all four subtypes of human dendritic cells in peripheral blood and within the tumor.


Financial resources/Grants

•   ICRF - Israel Cancer Research Fund grant (current funding)
•   VABC - Voices against brain cancer grant (current funding)
•   ICA - Israel Cancer Association grant (2011-2013)
•   MOH - Israeli Ministry of Health grant (2011-2013)

Collaborations

  • The Dept of Immunology – the Weizmann Institute of Science.
  • Advanced technologies center – Sheba Medical Center
  • Koret School of Veterinary Medicine - The Hebrew University, Beit Bagan


Team

Nati Shapira, MSc - researcher
Merav Bloch, MSc
Tal Alter, MSc student
Idan Ben Horin, MD
Ori Barzilay, MD

Anatoly Shinkarevsky, MSc student

Department details

+ 972-3-6972436
The Founders’ Building
Floor 6

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