SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R I M M U N O L O G Y P R O G R A M
2003
Yu, A, Zhou, J, Marten, N, Bergmann, CC,
Mammolenti, M, Levy, RB, and Malek, TR. Efficient
induction of primary and secondary T celldependent
immune responses in vivo in the
absence of functional IL-2 and IL-15 receptors.
Journal of Immunology 170:236-42, 2003.
HIGHLIGHTS/DISCOVERIES
• After allogeneic BMT, the recipient can resist
the engraftment of transplanted donor stem
cells by using immune responses, which do not
involve the two major pathways of T lymphocyte-mediated
killing. This is a surprising finding
and demonstrates that it is likely that for
some transplants, different pathways in the recipient
must be blocked to help the transplanted
bone marrow engraft.
• Lymphocytes that are added to donor stem cells
before transplant to help or facilitate the engraftment
by these stem cells after transplant,
use different functions for the purposes of: 1)
helping to “seed” the stem cells in the recipient,
and 2) helping to maintain their permanent
presence.
MATHIAS G. LICHTENHELD, M.D.
Associate Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
Cytotoxic lymphocytes defeat tumors and virus
infections. Their prevailing mechanism
to kill the diseased targets requires a unique organelle—the
cytotoxic granule. Perforin,
granzyme A, and granzyme B constitute the
prototypic killer molecules of the granule, which
collaborate to induce the target to commit suicide.
Researchers in Dr. Lichtenheld’s laboratory
investigate which genes and transcriptional
mechanisms promote the identity and function
of cytotoxic lymphocytes through their endowment
with cytotoxic granules. Recently, his laboratory
has shown that the activation and differentiation
of cytotoxic lymphocytes involves the Stat
signaling pathway and epigenetic controls of the
perforin gene. Interestingly, distal regulatory elements
rather than proximal promoter elements
are involved, suggesting long-range changes of
the chromatin structure, which are under investigation
along with the further characterization of
the far-distal enhanceosomes that may comprise a
locus control-like region. To study the hierarchy
of nuclear events induced during the differentiation
process, these researchers are characterizing
transcription factors differentially expressed in
cDNA subtractions and nuclear proteins differentially
present in proteomic analyses of 2D gels.
The functional analysis of the respective genes is
undertaken in transgenic mice and a unique
model cell line for the maturation process of cytotoxic
lymphocytes in which cytokine receptor
signals determine the maturation process of cytotoxic
lymphocytes but not their growth and survival.
Frequently, dysregulation of signaling pathways
is an essential component of hematopoietic
malignancies. A particular example is multiple
myeloma (MM), an incurable B-cell malignancy.
The goal of a new project is to develop preclinical
therapies defined at the molecular level. To that
end, Dr. Lichtenheld’s laboratory has shown that
the farnesyl transferase inhibitor R115777,
known to inhibit Ras signaling, kills MM cell
lines despite Ras prenylation, implying participation
of Ras-independent mechanism(s). This
mechanism requires activation of caspase-9. The
molecular components of this pathway and their
characterization are under investigation.
SELECTED PUBLICATIONS
2002
Zhou, J, Zhang, J, Lichtenheld, MG, and Meadows,
GG. A role for NF-kappa B activation in
perforin expression of NK cells upon IL-2 receptor
signaling. Journal of Immunology 169:1319-
25, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 113