tumor cell biology program - Sylvester Comprehensive Cancer Center

Kelvin P. Lee, M.D.
Associate Professor of
Microbiology and Immunology
DESCRIPTION OF RESEARCH
Work in Dr. Lee’s laboratory focuses
on the cells and molecules
that play central roles in initiating the
adaptive immune response. Understanding
these interactions is essential for
developing effective immune-based
therapies against cancer. At the cellular
level they are specifically studying the
dendritic cells (DC), which are thought
to be the most important professional
antigen presenting cell (APC). Because
DC monitor the local environment for
immunologic “danger” signals and control
what antigens are presented to T cells
to activate them, they are positioned to
regulate the initiation of immune responses.
Their work has examined how
DC arises from hematopoietic progenitors
and their intracellular/genetic characteristics.
They have previously reported
that activation of the protein kinase C
(PKC) intracellular signal transduction
pathway in human hematopoietic
CD34 + stem cells causes direct differentiation
to a pure population of DC. Thus,
PKC signaling specifically triggers the
DC differentiation “program” in these
cells. Additionally, specific isoforms of
PKC appear to regulate specific aspects
of DC differentiation. Ongoing studies
are seeking to completely characterize the
components of the PKC signaling pathway
and what genetic events are triggered
by this signal.
From a translational standpoint, researchers
in Dr. Lee’s lab have found that
in addition to normal cells, PKC activation
can drive DC differentiation in acute
and chronic myeloid leukemic blasts.
Because these “leukemic” DC retain the
ability to activate T cells and are endogenously
loaded with leukemia antigens,
they can potentially be used as “cellular”
anti-leukemia vaccines by reinfusion
back into patients. This work aims to
bring this approach to clinical trials.
In addition to cognate antigen presentation
by MHC to the T cell receptor
(signal 1), other key molecular
interactions underlie the ability of DC
to activate (or inactivate) T cells. The
most important of these is activation of
T cell costimulatory receptors (including
CD28, CD154 (CD40L), ICAM1)
by their APC counter-receptors (CD80,
CD86, CD40, LFA-3). They are studying
what role costimulation plays in activation
of immune responses (DNA
vaccination), and conversely in tolerance
induction (as therapy in organ transplantation
and as a strategy used by cancers
to evade immune destruction). These
researchers also are examining what role
of T cell activation plays in the pathogenesis
of opportunistic infections, which
are prevalent complications of immunosuppressive
chemotherapy regimens.
Hopefully, these studies will allow more
effective manipulation of immune responses
involved in all aspects of cancer
treatment.
PUBLICATIONS
St. Louis, D, Woodcock, J, Fransozo,
G, Blair, P, Carlson, LM, Murillo, ME,
Wells, M, Williams, A, Smoot, D,
Kaushal, S, Grimes, J, Harlan, DM,
Chute, J, June, CH, Siebenlist, U and
Lee, KP. Evidence from a human cell line
model for distinct intracellular signaling
pathways in CD34 + progenitor to dendritic
cell differentiation. Journal of Immunology
162:3237, 1999.
Schlienger, K, Craighead, N,
Francomano, T, Lee, KP, Levine, BL and
June, CH. Efficient priming of protein
antigen-specific human CD4(+) T cells
by monocyte-derived dendritic cells.
Blood 96:3490, 2000.
Tadaki, DK, Kirk, AD, Craighead,
N, Saini, A, Chute, JP, Lee, KP and
Harlan, DM. Costimulatory molecules
are active in the human xenoreactive T
cell response but not in NK mediated
cytotoxicity. Transplantation 70:162,
2000.
HIGHLIGHTS/DISCOVERIES
• Direct activation of protein kinase C
causes normal human hematopoietic
CD34 + stem cells to differentiate into
dendritic cells.
• Protein kinase C activation causes many
myeloid leukemias to differentiate into
immunologically functional “leukemic”
dendritic cells. These cells have
potential utility as “cellular” anti-leukemia
vaccines.
• T cell activation may play a critical role
in the pathogenesis of opportunistic
infections.
Robert B. Levy, Ph.D.
Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
Dr. Levy’s laboratory is studying the
immunological responses following
allogeneic bone marrow transplantation
(BMT), which determine the
success or failure of the hematopoietic
graft. The primary objective of these
studies is to define how different effector
molecules produced by transplanted
donor T cells and by barrier cells in the
recipient regulate the development of
graft versus host disease (GVHD) and
control hematopoietic engraftment, respectively.
The work concerning GVHD has
focused on elucidating the role of donormediated
cytotoxicity against recipient
cells following the transplant. Their findings
have demonstrated that differing
pathways of cytotoxicity play different
roles in the GVHD process. Granule
dependent cytotoxicity dependent on
perforin function is important in the
development and onset of the disease.
Cytotoxicity mediated by CD95L (FasL)
is an important pathway in the pathogenesis
occurring in the liver during
GVHD and also can contribute to cutaneous
GVHD. Most interestingly, even
when both of these molecular pathways
are absent in donor T cells (i.e., when
26
UM/Sylvester Comprehensive Cancer Center Scientific Report 2002