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
periments. This peptide inhibits tumor development
not only in the mammary cells transfected
with the secreted MUC1, but also provides protection
against a variety of other tumor types.
• The very important molecule MMP-9 has been
shown to be overproduced by T lymphocytes from
tumor bearing mice due in part to the overexpression
of vascular endothelial growth factor.
The intriguing possibility that this molecule
may be helping tumor spread is being evaluated.
THOMAS R. MALEK, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
The development of lymphocytes and the
regulation of the immune response are critically
controlled by cytokines that mediate their
function by binding to specific multi-subunit cell
surface receptors. Recent evidence by others has
established that the genetically inherited X-linked
severe combined immunodeficiency disease
(SCID) is the result of mutations in the γc cytokine
receptor subunit that is a shared component of
the receptors for interleukin-2 (IL-2), IL-4, IL-7,
IL-9, and IL-15. This genetic defect prevents the
function of these five cytokines, resulting in a
severe blockade in T-lymphocyte development
and a greatly impaired immune system. These
cytokines and receptors are also important regulators
of the peripheral immune compartment.
A long-term goal of Dr. Malek’s laboratory
is to understand the role of cytokine receptors,
especially the IL-2 receptor, in the regulation of
the immune system. A current research emphasis
is to establish the molecular basis by which the γc
subunit contributes to binding multiple cytokines
as a component of five cytokine receptors and to
determine the mechanism by which γc utilizing
cytokines control T-cell development and function.
Another major aim of his laboratory is to
study the interaction of tumor-specific T cells
with its cognate tumor to define the mechanisms
responsible for failed anti-tumor immunity and
to develop new strategies to more effectively engage
the immune system to reject tumors.
Related to these goals, progress has been
made in the following areas: 1) distinct functional
regions of the extracytoplasmic domain of
γc have been defined and demonstrate that IL-2
and IL-7 utilize largely overlapping sites within
γc; 2) a cytoplasmic subdomain of γc was identified
that is critical for rapid IL-2-induced receptor-mediated
endocytosis, which occurs by a
novel proteasome dependent pathway; 3) IL-7
and IL-15 were found to be the essential gc-dependent
cytokines important for thymic-dependent
T-cell development, while IL-2, IL-7, and
IL-15 are required for the full production of
intraepithelial T lymphocytes, a second anatomical
site of T-cell development; 4) separate cytoplasmic
domains of the IL-7Rα chain controlled
distinct activities during T-cell development,
while normal IL-7R-dependent thymic development
requires the integrated activity of all these
domains; 5) a novel and unexpected role for IL-2
in thymic development was uncovered that is essential
to prevent autoimmunity and is related to
the production of T regulatory cells; and 6) one
important reason for failed anti-tumor immunity
is that tumor-specific T cells are ignorant of the
growing tumor. Memory T cells, however, were
shown not to be ignorant and induced effective
anti-tumor immune responses. Importantly, a
dendritic cell (DC)-based vaccine potently functioned
to induce tumor immunity, which sometimes
may lead to the rejection of the tumor.
SELECTED PUBLICATIONS
2002
Olosz, F and Malek, TR. Structural basis for
binding multiple ligands by the common
cytokine receptor gamma-chain. Journal of Biological
Chemistry 277:12047-52, 2002.
Demirci, G, Gao, W, Zheng, XX, Malek, TR,
Strom, TB, and Li, XC. On CD28/CD40 ligand
costimulation, common gamma-chain signals,
and the alloimmune response. Journal of Immunology
168:4382-90, 2002.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004