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
affected by DR3 than CD4 cells. They concluded
that DR3 signals may be important in effector
responses to pathogens by shaping the ensuing
polarization toward TH2 or toward a mixed
TH1/TH2 response.
DR3 transgenic mice were highly susceptible
to antigen-induced airway hyper-reactivity in an
asthma model in mice and produced increased
quantities of interleukin-13 (IL-13) and eosinophils
in the lung upon antigen exposure by inhalation.
Transgenic mice expressing a dominant
negative form of DR3 showed increased resistance
to airway hyper reactivity when compared
to wild type mice. Similarly, a blocking anti-
TL1a antibody was able to ameliorate asthma in
wild type mice, indicating that DR3 and TL1a
are involved in the pathogenesis of asthma.
CD30—Governor of T Cells?
CD30-L knock-out mice, when challenged with
tumor secreted gp9-Ig, exhibit severely diminished
CD8 CTL expansion. When used as allogeneic
bone marrow graft recipients, collaboration
with the laboratory of Robert B. Levy, Ph.D.,
showed that CD30-L knock-out exhibit diminished
graft versus host disease in a MHC II mismatch.
CD30 is highly expressed on CD45-RO
memory cells and serves as a T-cell costimulator
and as a regulator of trafficking molecules and of
pro- and anti-apoptotic molecules. CD30 signals
lead to IL-13 and Ifn-g production. Researchers
in Dr. Podack’s laboratory are studying the function
of CD30 and its ligand in tumor rejection
following vaccination.
Immunotherapy for Advanced Non-Small Cell
Lung Carcinoma
To determine whether CD8-mediated immune
responses could be elicited in stage IIIB/IV nonsmall
cell lung carcinoma (NSCLC) patients, 19
subjects were immunized several times with allogeneic
NSCLC cells transfected with CD80
(B7.1) and HLA-A1 or A2. Patients enrolled
were matched or unmatched at the HLA A1 or
A2 locus and their immune response compared.
Immunization significantly increased the frequencies
of interferon-γ secreting CD8 T cells in
all but one patient in response to ex vivo challenge
with NSCLC cells. The CD8 response of
matched and unmatched patients was not statistically
different. NSCLC reactive CD8 cells did
not react to K562. Clinically, 6 of 19 patients
responded to immunization with stable disease or
partial tumor regression. The study demonstrates
that CD8 Ifn-γ responses against non-immunogenic
or immunosuppressive tumors can be
evoked by cellular vaccines even at advanced
stages of disease. The positive clinical outcome
suggests that non-immunogenic tumors may be
highly susceptible to immune effector cells generated
by immunization. Further trials with curative
intent are warranted.
Macrophage-Perforin, a New Member of the
Perforin/C9 Family of Proteins
Searching the genomic database with perforin as
query sequence, Dr. Podack and colleagues found
two novel members of the perforin family. Structure
analysis suggests that the novel members
have a typical pore-forming domain but that the
proteins themselves are membrane anchored. Expressed
sequence tags (EST) analysis suggests that
one new perforin member is expressed in trophoblast
cells, while the second member is expressed
in macrophages. The laboratory has cloned the
macrophage-perforin (MΦ-Pf) and fused a gfp
tag to it for ease of detection. Expression of MΦ-
Pf-gfp in NIH 3T3 cells and in 293T cells results
in fluorescence in the nucleus and in the cytoplasm.
Fluorescent cells, however, subsequently
round up and die, and after several days no fluorescence
is detected. The data suggest that expression
of MΦ-Pf leads to cell death, putatively by
ectopic expression of a pore former. The data further
suggest that MΦ-perforin and trophoblastperforin
have essential lytic functions that need to
be carefully regulated for expression. Dr. Podack’s
laboratory team is in the process of deleting MΦ-
Pf and trophoblast-Pf in order to discover their
physiological function.
118
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004