SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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T U M O R I M M U N O L O G Y P R O G R A M Malek, TR, Yu, A, Vincek, V, Scibelli, P, and Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167-78, 2002. Malek, TR. T helper cells, IL-2 and the generation of cytotoxic T-cell responses. Trends in Immunology 23:465-67, 2002. 2003 Molano, RD, Pileggi, A, Berney, T, Poggioli, R, Zahr, E, Oliver, R, Malek, TR, Ricordi, C, and Inverardi, L. Long-term islet allograft survival in nonobese diabetic mice treated with tacrolimus, rapamycin, and anti-interleukin-2 antibody. Transplantation 75:1812-19, 2003. Bathe, OF, Dalyot-Herman, N, and Malek, TR. Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment. BMC Cancer 3:21, 2003. HIGHLIGHTS/DISCOVERIES • Established that the essential non-redundant function of IL-2 is the development of CD4 + CD25 + T regulatory cells. ECKHARD R. PODACK, M.D., PH.D. Professor and Chairman of Microbiology and Immunology DESCRIPTION OF RESEARCH Induction of Immunity by Heat Shock Protein gp96-Ig Heat shock protein gp96 is a natural adjuvant and a peptide chaperone binding to antigen presenting cells (APC) inducing APC activation, maturation, and channeling gp96-associated peptides into the class I major histocompatibility complex (MHC) presentation pathway for priming CD8 cytotoxic T lymphocyte (CTL) responses. Gp96 is unique in that it provides antigenicity and peptide-specificity through its peptide chaperone function and adjuvanticity through its ability to bind to scavenging receptors and toll-like receptors (TLRs) and to activate APC. Realizing the potential of gp96 as a vaccine, Dr. Podack’s laboratory had previously created a gp96-Ig fusion protein that is secreted from tumor cells upon transfection. In murine studies, tumor secreted gp96-Ig induced specific CD8 cytotoxic T lymphocyte (CTL) expansion and, when used as vaccine, mediated tumor rejection and long lasting tumor immunity by CD8 cells with the help of natural killer (NK) cells. Murine preclinical data suggest that human tumor cells secreting gp96-Ig will be a powerful, therapeutic CD8 CTL vaccine, because gp96-Ig provides both the adjuvant effect and the specific peptides for dendritic cell (DC) activation and presentation. Tumor secreted gp96-Ig recruits and activates DC and NK cells, and causes CD8 CTL expansion. The molecular determinants of the three-way cell interaction are studied by Dr. Podack and his colleagues. The potential of gp96- Ig to break immune tolerance to tumors is also under investigation. Death Receptor and its Ligand TL1a Mediate TH2 Switch and Contribute to Asthma The biological function of death receptor 3 (DR3, TNFR-SF12) is not known. DR3- transgenes expressed on T cells were used to determine the physiological function of DR3, a member of the tumor necrosis factor (TNF)- receptor family expressing an intracellular death domain. The full-length form of DR3, a dominant negative form of DR3 (DR3-DN) lacking the intracellular death domain and an alternatively spliced form of DR3 (DR3-∆5, 6) lacking exon 5 and 6 encoding the fourth extracellular cysteine rich domain, was analyzed by Dr. Podack’s laboratory. Transgenic expression of DR3 on T cells mediated TH2 polarization of cytokine and antibody production upon T-cell activation and antigen exposure. In addition, DR3 partially inhibited T-cell receptor (TCR) driven proliferation of CD4 and CD8 cells and reduced total T cell numbers in lymphoid organs without inducing apoptosis. CD8 cells were more UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 117
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
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G L O S S A R Y IFN—interferon IL
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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