T L Whiteside

Universität Ulm, Ulm, Baden-Württemberg, Germany

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Publications (611)2606.55 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Background. p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial. Methods. Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1); additional T-helper(Th) tetanus toxoid peptide (Arm 2) or additional Th wt p53-specific peptide (Arm 3). Vaccine DC (vDC) were delivered to inguinal lymph nodes at 3 time points. Vaccine (vDC) phenotype, circulating p53-specific T-cells and regulatory T-cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared to those of DC1 generated with an alternative maturation regimen. Results. No grade II-IV adverse events were observed. Two-year disease-free survival (DFS) of 88% was favorable. p53-specific T-cell frequencies were increased post vaccination in 11/16 patients (69%), with IFN-γ secretion detected in 4/16 patients. Treg frequencies were consistently decreased (p=0.006) relative to pre-vaccination values. The phenotype and function of DC1 were improved relative to vDC. Conclusion. Adjuvant p53-specific vaccination of HNSCC patients was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients' DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
  • Cancer Immunology and Immunotherapy 11/2013; · 3.64 Impact Factor
  • Theresa L Whiteside
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    ABSTRACT: Regulatory T cells (Treg) play a key role in maintaining the balance of immune responses in human health and in disease. Treg come in many flavors and can utilize a variety of mechanisms to modulate immune responses. In cancer, inducible (i) or adaptive Treg expand, accumulate in tissues and the peripheral blood of patients, and represent a functionally prominent component of CD4+ T lymphocytes. Phenotypically and functionally, iTreg are distinct from natural (n) Treg. A subset of iTreg expressing ectonucleotidases, CD39 and CD73, is able to hydrolyze ATP to 5'-AMP and adenosine (ADO) and thus mediate suppression of those immune cells which express ADO receptors. iTeg can also produce prostaglandin E2 (PGE2). These iTreg, expanding in response to tumor antigens and cytokines such as TGF-β or IL-10, are presumably responsible for the suppression of anti-tumor immune responses and for successful tumor escape. On the other hand, in cancers associated with prominent inflammatory infiltrates, e.g., colorectal carcinoma or certain types of breast cancer, iTreg down-regulate excessive inflammation by producing ADO and/or PGE2 and protect the host from tissue injury and tumor development. Thus, iTreg utilizing the same adenosine pathway play a key but dual role in cancer, and their plasticity is controlled and driven by the microenvironment. Thus, monitoring for the frequency and functions of iTreg rather than nTreg is important in cancer. In addition, elimination of iTreg by various available strategies prior to immunotherapies may not be beneficial in all cases and needs to be undertaken with caution.
    Cancer Immunology and Immunotherapy 11/2013; · 3.64 Impact Factor
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    ABSTRACT: Background:Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined.Methods:Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg.Results:The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3(+)CD25(hi) Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3(+) Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3(+)CD4(+) Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg.Conclusion:These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ.British Journal of Cancer advance online publication, 29 October 2013; doi:10.1038/bjc.2013.645 www.bjcancer.com.
    British Journal of Cancer 10/2013; · 5.08 Impact Factor
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    ABSTRACT: Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemo-radiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients. The frequency and absolute numbers of CD4+, ATP-hydrolyzing CD4+CD39+ and CD8+ T cells and expression levels of CD39, CD25, TGF-β-associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients (29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT). All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n=15), NED (n=10) and NC (n=15), in vitro sensitivity of CD4+ T cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V- binding assays. CRT decreased the frequency of circulating CD4+ T cells (p<0.002) but increased that of CD4+CD39+ Treg (p≤0.001) compared to untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP and CD39 on Treg. In vitro, Treg were resistant to AICD or cisplatin but conventional CD4+ T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects up-regulated pro-survival proteins, while Tconv up-regulated pro-apoptotic Bax. Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of anti-tumor immune responses and recurrence in HNSCC.
    Clinical Cancer Research 10/2013; · 7.84 Impact Factor
  • Miroslaw J Szczepanski, Theresa L Whiteside
    Biomarkers in Medicine 08/2013; 7(4):575-8. · 3.22 Impact Factor
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    ABSTRACT: Background:Sepsis continues to be a leading cause of death in infants and children. Natural killer (NK) cells serve as a bridge between innate and adaptive immunity, yet their role in pediatric sepsis has not been well characterized.Methods:We tested the hypothesis that decreased NK cell cytotoxicity is a common feature of pediatric systemic inflammatory response syndrome (SIRS)/sepsis patients by measuring, using flow cytometry, NK cell cytotoxicity and cell surface phenotype in the peripheral blood of 38 pediatric intensive care patients who demonstrated signs and symptoms of either SIRS and/or sepsis.Results:NK cell cytotoxicity was significantly reduced in PBMC of pediatric SIRS/sepsis patients as compared to healthy controls, and the percentage of CD56(dim) CD16(+) cytotoxic NK cells in peripheral blood mononuclear cells (PBMC) was lower in patients with SIRS/sepsis than in normal donors. However, on a per cell basis, CD56(dim) CD16(+) NK cells in patients mediated cytotoxicity as well as those in normal donors.Conclusion:The NK cell dysfunction in pediatric SIRS/sepsis patients reflects a quantitative rather than a qualitative difference from normal.Pediatric Research (2013); doi:10.1038/pr.2013.121.
    Pediatric Research 07/2013; · 2.67 Impact Factor
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    ABSTRACT: Inducible regulatory T cells (iTregs, also called Tr1 cells) are generated in the periphery (circulation or tissue) of cancer patients upon the encounter of naïve CD4(+) T cells with tumor-associated antigens. As p53 is often inactivated by genetic or epigenetic events during oncogenesis, p53-induced Tr1 cells might play a key role in establishing immunosuppressive networks in cancer patients. Tr1 cells were generated by co-culturing circulating CD4(+)CD25(-) T cells with autologous immature dendritic cells pulsed with a wild-type (WT) p53-derived peptide or an unrelated peptide derived from mucin 1 (MUC1). The Tr1 phenotype and the specificity for p53 of these cells were confirmed by multicolor flow cytometry. Moreover, the Tr1 cell-mediated suppression of T-cell proliferation was evaluated by CFSE-based flow cytometry, while their ability to alter the T-cell cytokine profile by ELISA and Luminex assays. The capacity of p53-induced Tr1 cells to suppress the generation and function of cytotoxic T lymphcoytes (CTLs) was assessed by flow cytometry and ELISPOT. Of note, low doses of the p53-derived peptide (p53low) induced greater numbers of Tr1 cells than the same peptide employed at high doses (p53high). Moreover, Tr1/p53low cells not secreted higher levels of interleukin-10 and transforming growth factor β1, but also mediated more robust suppressive effects on CTL proliferation than Tr1/p53high cells. Tr1/p53low cells, Tr1/p53high cells, as well as Tr1 cells generated with low doses of an unrelated MUC1-derived peptide were equally effective in suppressing the expansion and antitumor activity of p53-reactive CTLs. p53low induced the expansion of highly suppressive p53-reactive Tr1 cells. However, the capacity of these Tr1 cells to suppress the generation and function of p53-reactive CTLs was independent of their antigen-specificity.
    Oncoimmunology. 07/2013; 2(7):e25514.
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    ABSTRACT: The role of the adenosine (ADO) suppression pathway, specifically CD39-expressing and CD73-expressing CD4 T cells in HIV-1 infection is unclear. We evaluated the frequency and numbers of CD4CD39 and CD4CD73 T cells, activated T cells, and plasma C reactive protein (CRP) levels in 36 HIV-1-positive individuals and 10 normal controls (NC). Low-level plasma viremia was evaluated using single copy assay. Mass spectrometry was used to measure hydrolysis of ATP by ectoenzyme-expressing CD4 T cells, whereas cyclic adenosine monophosphate (cAMP) levels were measured using enzyme immunoassay. Suppression of T-cell function by exogenous ADO and CD4CD73 T cells was tested by flow cytometry. CD39 and CD73 are expressed in different CD4 T-cell subsets. CD4CD73 T cells do not express CD25 and FOXP3, and their frequency and numbers were lower in HIV-1-positive individuals regardless of virologic suppression (P = 0.005 and P < 0.001, respectively). CD4CD73 numbers inversely correlated with CD4CD38DR (P = 0.002), CD8CD38DR T-cell frequency (P = 0.05), and plasma CRP levels (P = 0.01). Both subsets are required for hydrolysis of exogenous ATP to ADO and can increase CD4 T-cell cAMP levels when incubated with exogenous ATP. Low-level viremia did not correlate with activated T-cell frequency. In vitro, ADO suppressed T-cell activation and cytokine expression. CD4CD73 T cells suppressed T-cell proliferation only in the presence of exogenous 5'-AMP. The ADO-producing CD4CD73 subset of T cells is depleted in HIV-1-positive individuals regardless of viral suppression and may play a key role in controlling HIV-1-associated immune activation.
    AIDS (London, England) 06/2013; 27(10):1545-1555. · 4.91 Impact Factor
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    ABSTRACT: BACKGROUND: The prognosis of metastatic melanomas to the brain (MBM) is variable with prolonged survival in a subset. It is unclear whether MBM differ from extracranial metastases (EcM) and primary melanomas (PrM). METHODS: To study the biology of MBM, histopathologic analysis of tumor blocks from patients' craniotomy samples and whole-genome expression profiling (WGEP) with confirmatory immunohistochemistry were performed. RESULTS: High mononuclear infiltrate and low intratumoral hemorrhage were associated with prolonged overall survival (OS). Pathway analysis of WGEP data from 29 such craniotomy tumor blocks demonstrated that several immune-related BioCarta gene sets were associated with prolonged OS. WGEP analysis of MBM in comparison with same-patient EcM and PrM showed that MBM and EcM were similar, but both differ significantly from PrM. Immunohistochemical analysis revealed that peritumoral CD3(+) and CD8(+) cells were associated with prolonged OS. CONCLUSIONS: MBMs are more similar to EcM compared with PrM. Immune infiltrate is a favorable prognostic factor for MBM. Cancer 2013. © 2013 American Cancer Society.
    Cancer 05/2013; · 5.20 Impact Factor
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    ABSTRACT: Antibody-independent role of B cells in modulating T-cell responses is incompletely understood. Freshly-isolated or cultured B cells isolated from the peripheral blood of 30 normal donors were evaluated for CD39 and CD73 co-expression, the ability to produce 5'-AMP and adenosine (ADO) in the presence of exogenous(e) ATP as well as A1, A2A, A2B and A3 adenosine receptor (ADOR) expression. Human circulating B cells co-express ectonucleotidases, CD39 and CD73, hydrolyze exogenous ATP to 5'-AMP and ADO and express mRNA for A1R, A2AR and A3R. 2-chloroadenosine (CADO) inhibited B-cell proliferation and cytokine expression, and only A3R selective antagonist restored B-cell functions. This suggested that B cells utilize the A3R for autocrine signaling and self-regulation. mediated effects on B-cell growth ± ADOR antagonists or agonists were tested in CFSE assays. In co-cultures, resting B cells up-regulated functions of CD4(+) and CD8(+) T-cells. However, in vitro-activated B cells down-regulated CD73 expression, mainly produced 5'-AMP and inhibited T-cell proliferation and cytokine production. These B cells acquire the ability to restrict potentially harmful effects of activated T cells. Thus, B cells emerge as a key regulatory component of T cell-B cell interactions, and their dual regulatory activity is mediated by the products of ATP hydrolysis, 5'-AMP and ADO.
    Blood 05/2013; · 9.06 Impact Factor
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    ABSTRACT: PURPOSE: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T-lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. EXPERIMENTAL DESIGN: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC Class I-restricted melanoma peptides (12MP) to stimulate CTL (group A), plus a tetanus peptide (group B) or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6MHP alone (group D), in incomplete Freund's adjuvant (IFA) plus GM-CSF. CTL responses were assessed using an in vitro stimulated IFN-gamma ELIspot assay, and HTL responses using proliferation assay. RESULTS: In groups A-D, respectively, CTL response rates to 12MP were 43%, 47%, 28%, and 5%, and HTL response rates to 6MHP were in 3%, 0%, 40% and 41%. Best clinical response was partial response (PR) in 7/148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6MHP was significantly associated with both clinical response (p=0.036) and OS (p=0.004). CONCLUSIONS: Each vaccine regimen was immunogenic, but melanoma helper peptides did not augment CTL responses to 12MP. The association of survival and immune response to 6MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies.
    Clinical Cancer Research 05/2013; · 7.84 Impact Factor
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    ABSTRACT: In patients with Ovarian Cancer (OvCa) exosomes released by tumor cells are present in the plasma and could be involved in tumor progression. This study examines the association between the exosome presence/protein content in plasma of OvCa patients and disease outcome, response to standard therapy and/or tumorresistance to therapies in patients studied at diagnosis and also serially during and after therapy. Exosomes were purified from OvCa patients' plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC) using ultracentrifugation. Exosomes were visualized by scanning electron microscopy. Their protein content was measured. The presence of MAGE 3/6 and TGF-β1 in exosomes was evaluated in Western blots. The OvCa patients' plasma contained higher levels of exosomal proteins (p<0.05) compared to those isolated from plasma of patients with benign tumors or NC. Exosomes isolated from OvCa patients's plasma carried TGF-β1 and MAGE3/6, which distinguished OvCa patients from those with benign tumors and NC. High protein levels of exosomes were seen in newly diagnosed patients; however in advanced stages of OvCa patients the protein content of isolated exosomes was significantly higher than that of early stages. The exosome levels variably changed during/after chemotherapy, and correlations between the changes in exosomal protein levels and clinical data suggested that the protein content of exosomes might be useful in predicting responses to therapy and prognosis in OvCa patients. Analysis of plasma exosomes levels offers a novel approach to diagnosis and monitoring response to therapies in OvCa patients.
    Gynecology & obstetrics (Sunnyvale, Calif.). 04/2013; Suppl 4:3.
  • Theresa L Whiteside
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    ABSTRACT: Body fluids of cancer patients contain TEXs (tumour-derived exosomes). Tumours release large quantities of TEXs, and the protein content of exosome or MV (microvesicle) fractions isolated from patients' sera is high. TEXs down-regulate functions of immune cells, thus promoting tumour progression. We isolated TEXs from tumour cell supernatants and sera of patients with solid tumours or AML (acute myelogenous leukaemia). The molecular profile of TEXs was distinct from that of circulating exosomes derived from normal cells. TEXs were co-incubated with activated T-cells, conventional CD4+CD25neg T-cells or CD56+CD16+ NK (natural killer) cells respectively. TEXs down-regulated CD3ζ and JAK3 (Janus kinase 3) expression in primary activated T-cells and mediated Fas/FasL (Fas ligand)-driven apoptosis of CD8+ T-cells. TEXs promoted CD4+CD25neg T-cell proliferation and their conversion into CD4+CD25hiFOXP3+ (FOXP3 is forkhead box P3) Treg cells (regulatory T-cells), which also expressed IL-10 (interleukin 10), TGFβ1 (transforming growth factor β1), CTLA-4 (cytotoxic T-lymphocyte antigen 4), GrB (granzyme B)/perforin and effectively mediated suppression. Neutralizing antibodies specific for TGFβ1 and/or IL-10 inhibited the ability of TEXs to expand Treg cells. TEXs obtained at diagnosis from AML patients' sera were positive for blast-associated markers CD33, CD34, CD117 and TGFβ1, and they decreased cytotoxic activity of NK cells isolated from NC (normal control) donors, induced Smad phosphorylation and down-regulated NKG2D receptor expression. Correlations between the TEX molecular profile or TEX protein levels and clinical data in cancer patients suggest that TEX-mediated effects on immune cells are prognostically important. In contrast with exosomes released by normal cells, TEXs have immunosuppressive properties and are involved in regulating peripheral tolerance in patients with cancer.
    Biochemical Society Transactions 02/2013; 41(1):245-51. · 2.59 Impact Factor
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    ABSTRACT: PURPOSE: Patients with cancer have an increased frequency of circulating apoptosis-sensitive CD8(+)CCR7(neg) T cells and few CD8(+)CCR7(+) T cells versus normal controls. The functional and clinical significance of this imbalance was investigated using peripheral blood of patients with squamous cell carcinoma of the head and neck (HNSCC).EXPERIMENTAL DESIGN: The frequency of circulating CD8(+) T cells co-expressing CCR7, CD45RO, CD28, and Annexin V (ANXV) was evaluated in 67 patients and 57 normal controls by flow cytometry. Spearman rank correlations among immunophenotypic profiles were analyzed. Recursive partitioning classified subjects as patients or normal controls based on CD8(+)CCR7(+) T-cell percentages. Kaplan-Meier plots estimated disease-free survival (DFS).RESULTS: The CD8(+)CCR7(+) T-cell frequency was low, whereas that of total CD8(+)CCR7(neg) and ANXV-binding CD8(+)CCR7(neg) T cells was higher in patients with HNSCC than in normal controls (P < 0.001-0.0001). ANXV binding correlated with the absence of CCR7 on CD8(+) T cells (P < 0.001). ANXV binding was negatively correlated with the CD8(+)CD45RO(neg)CCR7(+) (T(N)) cell frequency (P < 0.01) but positively correlated (P < 0.01) with that of CD8(+)CD45RO(+)CCR7(+) (T(CM)) T cells and of the two CCR7(neg) subsets (T(PM) and T(TD)). In recursive partitioning models, the CD8(+)CCR7(+) T-cell frequency of 31% distinguished patients from normal controls with 77% to 88% accuracy after cross-validation. In 25 patients tested before any therapy, the CD8(+)CCR7(+) T-cell frequency of less than 28% predicted disease recurrence within 4 years of definitive therapy (P < 0.0115).CONCLUSION: The CD8(+)CCR7(+) T-cell frequency in HNSCC patients' blood tested at diagnosis can discriminate them from normal controls and predicts disease recurrence. Clin Cancer Res; 19(4); 1-11. ©2012 AACR.
    Clinical Cancer Research 01/2013; · 7.84 Impact Factor
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    ABSTRACT: In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy.
    PLoS ONE 01/2013; 8(2):e47234. · 3.73 Impact Factor
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    Theresa L Whiteside, Edwin K Jackson
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    ABSTRACT: Regulatory T cells (Treg) play a key role in maintaining the balance of immune responses in human health and in disease. Treg come in many flavors and can utilize a variety of mechanisms to modulate immune responses. In cancer, inducible (i) or adaptive Treg expand, accumulate in tissues and peripheral blood of patients, and represent a functionally prominent component of CD4+ T lymphocytes. Phenotypically and functionally, iTreg are distinct from natural (n) Treg. A subset of iTreg expressing ectonucleotidases CD39 and CD73 is able to hydrolyze ATP to 5'-AMP and adenosine (ADO) and thus mediate suppression of those immune cells which express ADO receptors. iTreg can also produce prostaglandin E2 (PGE2). The mechanisms responsible for iTreg-mediated suppression involve binding of ADO and PGE2 produced by iTreg to their respective receptors expressed on T effector cells (Teff), leading to the up-regulation of adenylate cyclase and cAMP activities in Teff and to their functional inhibition. The potential for regulating these mechanisms by the use of pharmacologic inhibitors to relieve iTreg-mediated suppression in cancer suggests the development of therapeutic strategies targeting the ADO and PGE2 pathways.
    Frontiers in Immunology 01/2013; 4:212.
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    Theresa L Whiteside
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    ABSTRACT: Recent technical improvements in evaluations of immune cells in situ and immune monitoring of patients with cancer have provided a wealth of new data confirming that immune cells play a key role in human cancer progression. This, in turn, has revived the expectation that immune endpoints might serve as reliable biomarkers of outcome or response to therapy in cancer. The recent successes in linking the T-cell signature in human colorectal carcinoma (CRC) with prognosis have provided a strong motive for searching for additional immune biomarkers that could serve as intermediate endpoints of response to therapy and outcome in human cancers. A number of potentially promising immune biomarkers have emerged, but most remain to be validated. Among them, the B-cell signature, as exemplified by expression of the immunoglobulin G kappa chain (IGKC) in tumor-infiltrating lymphocytes (TIL), has been validated as a biomarker of response to adjuvant therapy and better survival in patients with breast carcinoma and several other types of human solid tumors. Additional immune endpoints are being currently tested as potentially promising biomarkers in cancer. In view of currently growing use of immune cancer therapies, the search for immune biomarkers of prognosis are critically important for identifying patients who would benefit the most from adjuvant immunotherapy.
    Frontiers in Oncology 01/2013; 3:107.
  • Theresa L Whiteside, Soldano Ferrone
    Clinical Cancer Research 12/2012; · 7.84 Impact Factor
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    ABSTRACT: OBJECTIVES: PRAME (Preferentially Expressed Antigen in Melanoma) is a tumor-associated antigen recognized by immunocytes, and it induces cytotoxic T cell-mediated responses in melanoma. PRAME expression in tumors interferes with retinoic acid receptor (RAR) signaling thus promoting tumor progression. Here, we study PRAME expression in head and neck squamous cell carcinoma (HNSCC) to determine its potential clinical significance. MATERIALS AND METHODS: PRAME expression in HNSCC was evaluated by immunohistochemistry in tissue microarrays of primary tumors (n=53), metastatic lymph nodes (n=8) and normal oral mucosa (n=11). Biopsies of dysplastic oral lesions (n=12) were also examined. PRAME expression levels in tissues were correlated with markers of poor prognosis in HNSCC. PRAME mRNA in HNSCC cell lines and in normal immortalized human keratinocytes (HaCaT cell line) was measured by qRT-PCR, and the protein expression by flow cytometry and western blots. RESULTS: PRAME was expressed in HNSCC cell lines and HNSCC lesions. PRAME expression in dysplastic mucosa was variable. No or only weak expression was found in normal cells or tissues. PRAME expression levels significantly correlated with the tumor grade, size, nodal involvement and the clinical status of HNSCC patients. CONCLUSIONS: Elevated PRAME expression associates with clinicopathologic markers of poor outcome in HNSCC and might identify potential candidates with pre-cancerous lesions for chemoprevention with retinoids.
    Oral Oncology 08/2012; · 2.70 Impact Factor

Publication Stats

15k Citations
2,606.55 Total Impact Points


  • 2013
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • Pediatrics
      Hershey, PA, United States
    • Universitätsklinikum Gießen und Marburg
      Marburg, Hesse, Germany
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2012–2013
    • Medical University of Warsaw
      • Department of Otolaryngology
      Warszawa, Masovian Voivodeship, Poland
    • Wojskowy Instytut Medyczny
      Warszawa, Masovian Voivodeship, Poland
    • University of Kragujevac
      Krabujevac, Central Serbia, Serbia
  • 2009–2013
    • Poznan University of Medical Sciences
      • Department of Clinical Immunology
      Posen, Greater Poland Voivodeship, Poland
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 1975–2013
    • University of Pittsburgh
      • • Department of Pathology
      • • Department of Otolaryngology
      • • School of Medicine
      • • Department of Surgery
      • • Pittsburgh Cancer Institute
      • • Department of Medicine
      • • Division of Clinical Immunopathology
      Pittsburgh, Pennsylvania, United States
  • 2010–2012
    • University of Duisburg-Essen
      Essen, North Rhine-Westphalia, Germany
  • 2011
    • Medical University of Graz
      • Institut für Pathologie
      Graz, Styria, Austria
  • 1999–2007
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 1997–2007
    • Heinrich-Heine-Universität Düsseldorf
      • Frauenklinik
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2006
    • Carnegie Mellon University
      • Molecular Biosensor and Imaging Center
      Pittsburgh, PA, United States
  • 1992–2006
    • Università degli Studi di Torino
      • • Dipartimento di Scienze Mediche
      • • Dipartimento di Scienze Cliniche e Biologiche
      Torino, Piedmont, Italy
  • 1999–2004
    • Tel Aviv University
      • Department of Epidemiology
      Tell Afif, Tel Aviv, Israel
  • 2003
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Universidade Federal do Rio Grande do Sul
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 2001–2003
    • University of Louisville
      Louisville, Kentucky, United States
    • Harvard Medical School
      • Department of Orthopaedic Surgery
      Boston, Massachusetts, United States
  • 1998–2001
    • National Cancer Institute (USA)
      Maryland, United States
    • Ludwig-Maximilian-University of Munich
      • Department of Otorhinolaryngology
      München, Bavaria, Germany
  • 2000
    • Kumamoto University
      • Center for AIDS Research
      Kumamoto-shi, Kumamoto Prefecture, Japan
  • 1997–2000
    • Georgetown University
      • • Department of Radiation Medicine
      • • Department of Pharmacology
      Washington, D. C., DC, United States
  • 1996
    • Università degli studi di Cagliari
      Cagliari, Sardinia, Italy
  • 1995
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1994
    • Pittsburg State University
      Kansas, United States
    • Goethe-Universität Frankfurt am Main
      • Zentrum der Inneren Medizin
      Frankfurt am Main, Hesse, Germany
  • 1992–1993
    • Toyama Medical and Pharmaceutical University
      Тояма, Toyama, Japan
  • 1991–1993
    • Victor Babes National Institute of Pathology
      Bucureşti, Bucureşti, Romania
  • 1989
    • Pittsburgh Institute of Aeronautics
      Pittsburgh, Pennsylvania, United States
  • 1986–1988
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
    • University of Lausanne
      Lausanne, Vaud, Switzerland