International Summer Science Institute Young@Science, Weizmann Institute of Science
Cancer Immunology Basic Mechanisms Behind Tumor
Rejection And Tumor Growth
Mentor: Ofir Goldberger
Supervisor: Prof. Lea Eisenbach
Dept. of Immunology
Address: Wolfson bldg. room 220, Tel: 2881
E-mail: ofir.goldberger@weizmann.ac.il
Background
Malignant cancer is defined by the NIH as abnormal cells which divide without
control or order and may invade and damage other tissues and organs.
The adaptive cellular immune system is theoretically capable of discriminating
between transformed (tumor) cells and normal tissue cells and subsequently attacking
the tumor cells. The main participants in this scenario are white blood cells called
lymphocytes. A population of lymphocytes called T cells can identify the tumor by
recognizing a short protein sequence (called a peptide) presented on top of a special
molecule (MHC class I) on the cell surface. The T cells perform this interaction via
the T cell receptor (TCR) which can recognize only one such peptide-MHC complex.
Since there are billions of different T cells in our bodies, each individual possesses the
potential to recognize at least that many different peptides.
The ability of T cells to kill tumor cells has been shown in numerous scenarios
in-vitro as well as in-vivo in mice. However, attempts to use lymphocytes for cancer
immunotherapy in patients have, so far, been mostly unsuccessful.
Research Goal
The predominant dogma predicts that increasing the number of T cells that can
recognize (and potentially kill) tumor cells will lead to the eradication of the tumor.
Under this assumption, much effort has been directed by the research community at
methods which may increase the number of such tumor-specific T cells. Such
methods include various immunization techniques and other ex-vivo treatments of
1
www.weizmann.ac.il/young
International Summer Science Institute Young@Science, Weizmann Institute of Science
T cells. However, our lab showed that increasing the number of tumor specific T cells
even to 100% of the total T cell population is not sufficient to destroy the tumor.
We have identified a tumor escape mechanism known as antigen silencing, which
occurs in the tumor model we investigate. We now seek to better characterize this
antigen silencing mechanism both at the DNA level and by describing the kinetics of
this phenomena.
Methodology
To study this lymphocyte – tumor interaction, we employ a transgenic mouse / tumor
system:
Transgenic tumor: The MO5 mouse melanoma (skin cancer) tumor cell line has been
transfected with the chicken ovalbumin gene. This tumor expresses an ovalbumin
derived peptide SIINFEKL which binds to an MHC class I molecule of type H-2Kb
with very high affinity.
Transgenic mouse: Mice of a strain called OT-I are transgenic to the T cell receptor
which recognizes the SIINFEKL peptide when it is presented on the H-2Kb MHC
class I molecule.
A scenario can be envisioned in which the OT-I T cells recognize the SIINFEKL
peptide on the H-2Kb molecule on the surface of the MO5 tumor and kill it. The
prediction from this simple model is, therefore, that an MO5 tumor cannot be
implanted in an OT-I mouse. However, this prediction was proven false by us and
opened a window into the question of tumor – T cell interactions and immune escape
by the tumor.
Tentative Research Plan
1. We will remove tumor grown on OT-I mice and investigate antigen silencing by
RT-PCR (Reverse Transcription Polymerase Chain Reaction).
2. We will perform a series of FACS (Fluorescence Activated Cell Sorting)
experiments to detect localization of T cells in tumor bearing mice.
• This research plan is tentative and partial since new and current data dictates the
experiment flow.
• Some work with mice may be involved but is not compulsory.
2
www.weizmann.ac.il/young
International Summer Science Institute Young@Science, Weizmann Institute of Science
Recommended Readings
Cancer immunotherapy: moving beyond current vaccines. Rosenberg SA, Yang JC,
Restifo NP. Nat Med. 2004 Sep;10(9):909–15.
Human tumor-specific T lymphocytes: does function matter more than number? Curr
Opin Immunol. 2005 Jun;17(3):320–5.
Note: Read the papers well but do not dwell into details, rather focus on
comprehending the basic mechanisms at work.
3
www.weizmann.ac.il/young