bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B6: Myeloid-derived suppressor cells from melanoma patients suppress T cell proliferation and are associated with a shorter disease-free interval.
Authors: McCarter Martin D. , Jordan Kimberly 
Published: August 2014

Abstract
Immune therapies such as vaccines, immune stimulators (IL-2), and immune checkpoint regulators (anti-CTLA-4) for melanoma elicit an initial robust immunologic response to the tumor in some patients, however, the majority ultimately go on to die of their disease. This suggests that tumor eventually develop escape mechanisms meant to evade or defeat the intrinsic immune response. Myeloid-derived suppressor cells (MDSCs) have been reported in melanoma and other cancer patients and may contribute to immune suppression or counter-regulatory responses. The aim of this project was to assess the potential role of circulating MDSCs in mediating immune suppression in advanced stage melanoma patients.
Methods: MDSC populations (DC14+ Lin-HLA-DR- , Lin-HLA-DR- CD11b+ CD33+) were isolated from patients with (stage I n=20, stage IV n=35)or without (n=15) melanoma. Isolated MDSC's were mixed with allogeneic CFSE-labeled T cells for a 4 day mixed lymphocyte reaction (MLR). T cell activation and proliferation were quantified.
Results: Stage IV melanoma patients have increased expression (2-3 times) of some MDSC populations (Lin-HLA-DR- CD11b+ CD33+) in the circulation compared to normal and stage I melanoma patients. By MLR, these MDSC's significantly suppressed T cell proliferation (40-50% reduction) and markers of activation (20%) to a greater extent than the same population of MDSC's for normal controls. Inhibiting nitric oxide failed to restore T-cell proliferation. A shorter disease free interval is associated with increased expression of CD33+ MDSC in the circulation.
Conclusion: MDSC populations are increased in the peripheral circulation of stage IV melanoma patients and these cells actively suppress T cell proliferation. Efforts are underway to better understand the melanoma related factors responsible for the induction of MDSC's and the mechanism by which these cells suppress T-cell proliferation.
Citation Format: Martin D. McCarter, Kimberly Jordan. Myeloid-derived suppressor cells from melanoma patients suppress T cell proliferation and are associated with a shorter disease-free interval. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B6.
Abstract B62: miR-124 systemically enhances antitumor clearance by inhibiting STAT3 signaling and reversing glioma-associated immune suppression.
Authors: Wei Jun , Kong Ling-Yuan , Wang Fei , Xu Shuo , Doucette Tiffany , Ferguson Sherise D. , Yang Yuhui , McEnery Kayla , Jethwa Krishan , Gjyshi Olsi , Qiao Wei , Lang Frederick , Rao Ganesh , Fuller Greg N. , Calin George A. , Heimberger Amy B. 
Published: August 2014

Abstract
MicroRNAs (miRs) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immune suppression is largely unknown. In this study, we evaluated miRNAs that are preferentially down-regulated in glioblastoma and that interact with immune suppressive pathways as potential new therapeutics. On the basis of miRNA-gene expression libraries of glioblastoma, tissue microarrays, and molecular modeling, we selected miR-124 as the lead candidate for modulating signal transducer and activator of transcription 3 (STAT3) signaling, a key pathway mediating immune suppression of the tumor microenvironment. Upon up regulating miR-124 in glioma cancer stem cells (gCSCs), the STAT3 pathway was inhibited and the miR-124 reversed gCSC-mediated immune suppression of T cell proliferation and Th1 polarization and decreased gCSC-induced Foxp3+ regulatory T cells (Tregs). Treatment of immune-suppressed glioblastoma patient T cells with miR-124 induced marked effector response including up regulation of IL-2, IFN-γ and TNF-α. Both systemic administration of miR-124 or adoptive miR-124 transfected T cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in nude murine systems. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasm treatment by exploiting the immune system to mediate direct tumor cytotoxicity.
Citation Format: Jun Wei, Ling-Yuan Kong, Fei Wang, Shuo Xu, Tiffany Doucette, Sherise D. Ferguson, Yuhui Yang, Kayla McEnery, Krishan Jethwa, Olsi Gjyshi, Wei Qiao, Frederick Lang, Ganesh Rao, Greg N. Fuller, George A. Calin, Amy B. Heimberger. miR-124 systemically enhances antitumor clearance by inhibiting STAT3 signaling and reversing glioma-associated immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B62.
Abstract B67: Galectin-1 expression related to hypoxia in primary human melanoma as a driver for metastatic progression. A target to promote anticancer immunotherapy.
Authors: Ralph Stephen J. , Ito Koichi , Wachter Bernadette , Onturk Selda , Wilmott James , Hersey Peter 
Published: August 2014

Abstract
Galectin-1 is a major protein secreted by the majority of cancer types which is induced by HIF and plays important roles in the tumor microenvironment protecting against anticancer immune cell attack and from reactive oxygen species production. We have shown this protein to be more highly expressed within hypoxic regions of primary melanoma. Galectin-1 expression is critical for protecting endothelial cells in tumor angiogenesis and for promoting tumor metastasis. More recently, we have shown that inhibiting this protein using small drug molecules significantly enhances chemotherapeutic access inside tumors by promoting leakiness and facilitates TIL access inside tumors to kill cancer cells. When galectin-1 blocking drugs are used in combination as a triple therapy with modified whole cancer cell vaccines plus anti-CTLA4 Ig, this provides synergistic enhancements increasing CD8+ CTL anticancer TIL responses to inhibit cancer growth in a range of different mouse tumor models.
Citation Format: Stephen J. Ralph, Koichi Ito, Bernadette Wachter, Selda Onturk, James Wilmott, Peter Hersey. Galectin-1 expression related to hypoxia in primary human melanoma as a driver for metastatic progression. A target to promote anticancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B67.
Abstract B76: CD8+FoxP3+ T cells: A new player in the immune response to ovarian cancer.
Authors: Kost Sara E.F. , deLeeuw Ronald J. , Nelson Brad H. 
Published: August 2014

Abstract
Introduction: Tumor-infiltrating lymphocytes (TIL) are an important prognostic indicator in high-grade serous ovarian carcinoma (HGSC). Certain types of TIL (in particular CD8+ effector T cells) predict better outcomes, whereas others (most notably CD4+CD25+FoxP3+ regulatory T cells or Tregs) predict worse outcomes. An unconventional subset of CD8+FoxP3+ T cells has been widely reported in autoimmunity. While the functional significance of CD8+FoxP3+ TIL remains poorly understood, in a murine tumor model they were associated with effective anti-tumor responses.
Hypothesis: CD8+FoxP3+ TIL are present in HGSC and correlate with effector TIL and increased patient survival.
Experimental Design: Multi-parameter flow cytometry and immunohistochemistry (IHC) were performed on cohorts of 12 and 45 primary HGSC specimens, respectively, to enumerate and locate CD8+FoxP3+ TIL. For IHC, intraepithelial versus stromal location was determined by staining adjacent sections for the epithelial marker cytokeratin. Multi-color staining was resolved using the Nuance™ multispectral imaging system in conjunction with Metamorph software. Survival analysis will be performed by staining a cohort of 200 cases of HGSC.
Results: By flow cytometry, CD8+FoxP3+ cells were found in variable proportions between HGSC cases, representing 1.3 - 7.9% of CD8+ TIL and 1.3 - 25.8% of FoxP3+ TIL. By IHC, CD8+FoxP3+ TIL were found together with CD8+FoxP3- and CD4+FoxP3+ TIL in epithelial and stromal tumor regions and represented up to 19% of the FoxP3+ population. Interestingly, the majority of CD8+FoxP3+ TIL were also found to be TIA-1+KI67-, consistent with an active role in the anti-tumor response.
Conclusions: CD8+FoxP3+ TIL are a component of the host immune response to HGSC. Survival analysis is ongoing and will determine whether CD8+FoxP3+ T cells enhance or inhibit tumor immunity. Improved understanding of this new TIL subset will inform future immunotherapy strategies for this challenging malignancy.
Citation Format: Sara E.F. Kost, Ronald J. deLeeuw, Brad H. Nelson. CD8+FoxP3+ T cells: A new player in the immune response to ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B76.
Abstract B91: Tasquinimod targets immuno-suppressive myeloid cell populations and enhances immunotherapy in murine prostate cancer models.
Authors: Shen Li , Miles Kiersten Marie , Ciesielski Michael , Ellis Leigh , Fenstermaker Robert , Pili Roberto 
Published: August 2014

Abstract
Purpose: A major component of the immunosuppressive environment responsible for immune tolerance in cancer is represented by myeloid cell populations such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs). These cells facilitate carcinogenesis and tumor progression by impairing T and NK cells activation and contributing to modulate angiogenesis. Tasquinimod is an anti-angiogenic and immunomodulatory agent that has shown clinical benefit in patients with prostate cancer. This agent has been found to bind to the inflammatory protein S100A9, to block the interaction of S100A9 with myeloid cells surface receptors, and therefore has the potential to affect accumulation and function of these cells.
Experiments and Objectives: We tested tasquinimod in combination with a vaccine therapy in two castration resistant, syngenic transplantable murine prostate cancer models: CR Myc-Cap and TRAMP-C2. This study had the following objectives: 1) to explore tasquinimod's novel immunomodulatory activities and underlining mechanism; 2)To investigate whether tasquinimod inhibits the induction and function of immunosuppressive myeloid cell populations; 3) To assess whether tasquinimod can facilitate vaccine therapy in the castrate resistant prostate cancer models.
Results: We observed that the peripheral MDSCs (in blood and spleen) dramatically increased in tumor bearing mice as compared to naïve mice. The MDSCs number increase correlated with disease progression in the transgenic model. Tasquinimod treatment depleted Gr1-CD11b+, Ly6G-CD11b+ (monocytic MDSCs) myeloid cells and M2 macrophages in peripheral sites, and reduced Gr1+CD11b+ MDSCs infiltrates in the tumors. In addition, tasquinimod (10mg/kg) dramatically improved tumor-specific immune responses, including the granzyme B expression in CD8 cells and cytotoxicity of splenocytes, and enhanced anti-tumor activity of a survivin-mimetic peptide vaccine.
Conclusions: 1. MDSCs accumulate in prostate cancer models suggesting that MDSCs may contribute to immune tolerance in prostate cancer. 2. Tasquinimod reduces immunosuppressive MDSCs and M2 macrophage and may facilitate vaccine therapy by enhancing cell-mediated cytotoxic tumor cell killing and the anti-tumor immune response.
Citation Format: Li Shen, Kiersten Marie Miles, Michael Ciesielski, Leigh Ellis, Robert Fenstermaker, Roberto Pili. Tasquinimod targets immuno-suppressive myeloid cell populations and enhances immunotherapy in murine prostate cancer models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B91.
Abstract IA16: Engineered T cell therapies for cancer.
Authors: June Carl H. 
Published: August 2014

Abstract
Chimeric antigen receptors (CARs) combine an antigen recognition domain of a specific antibody with a intracellular signaling domains into a single engineered protein. CD19 is an ideal target for CARs since expression is restricted to normal and malignant B cells. In preclinical studies, inclusion of the CD137 (4-1BB) signaling domain results in remarkable antitumor activity and in vivo persistence of anti-CD19 CARs. We have previously reported dramatic in-vivo expansion, persistence and anti-tumor activity of CAR modified autologous T cells targeted to CD19 (CART19 cells) in 3 patients with CLL with relatively short follow up (Porter, et al NEJM 2011; Kalos et al Sci Trans Med 2011). Currently, 11 patients have been treated with CART19 cells. There were 9 adults (median age 65 years (range 51-78)) treated for relapsed, refractory and high risk CLL and two pediatric cases treated for relapsed refractory pre-B cell ALL. CLL patients had received a median of 5 prior regimens excluding single agent rituxumab (range 2-10) and all had active disease at the time of cell infusion. The pediatric patients with ALL had chemotherapy refractory relapse, and one was resistant to allogeneic transplantation and CD19 directed blinotumomab. A median of 7.5 x 10^8 total cells (range 1.7-50) corresponding to 1.45 (range 0.14-5.9 x 108) genetically modified cells were infused. In the patients in complete remission, CAR modified CART19 cells are detectable in the peripheral blood by flow cytometry at the most recent follow up for at least 2 years. All patients in CR have B cell aplasia. No patient with CR has progressed.
Citation Format: Carl H. June. Engineered T cell therapies for cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA16.
Abstract IA23: Cervical tissue T cells in HPV disease.
Authors: Trimble C.L. , Teague J. , Wu T.C. , Clark R.A. 
Published: August 2014

Abstract
Despite the availability of preventative vaccines, human papillomaviruses (HPVs) cause more cancers than any other virus. Like other viral pathogens that cause human cancers, most HPV infections do not cause overt harm, let alone symptoms. Indeed, in immune-competent persons, most genital infections are eventually cleared. Nonetheless, the incidence of HPV-associated cancers in anatomic sites for which no screening algorithms have been validated is rising steadily. Preinvasive, intraepithelial lesions are associated with integration of the HPV genome into the host genome, and subsequent expression of the viral oncoproteins, E6 and E7, which are required for disease initiation and persistence. These true tumor-specific antigens provide non-“self” targets for immune therapies. The relatively indolent clinical course of preinvasive lesions, and tissue tropism of HPV infections provide opportunities to identify and treat early stage disease.
In cervical HPV disease, a subset of high grade dysplastic lesions, cervical intraepithelial neoplasia grade 3 (CIN3), do in fact undergo complete regression, which is presumably immunologically mediated. However, T cell responses to viral antigens, measured in the blood, have not been informative with respect to immune responses in the cervical mucosa.
Our team has been studying strategies to enhance the quality and magnitude of immune responses to HPV antigens. Ongoing clinical trials testing therapeutic vaccination and strategies to manipulate the lesion microenvironment to enhance homing and access of immune effector cells will be discussed. The design of these trials has been informed by studies of tissue-resident T cells in normal cervical mucosa, and by changes identified in dysplastic mucosa, both in lesions that regress, and in those that do not, in the course of a defined, prospective study window. Changes in the composition and distribution of tissue T cells postvaccination will be presented. Strategies to modify the stromal compartment of HPV lesions to promote lesion clearance will also be discussed.
Citation Format: C.L. Trimble, J. Teague, T.C. Wu, R.A. Clark. Cervical tissue T cells in HPV disease. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA23.
Abstract IA8: The interplay of inflammation and cancer.
Authors: Dranoff Glenn 
Published: August 2014

Abstract
Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits. We demonstrated that vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplishes clinically significant tumor destruction with minimal toxicity in a majority of stage IV metastatic melanoma and some advanced ovarian carcinoma patients. The detailed analysis of patients achieving sustained clinical benefits from these therapies illustrated the importance of a coordinated cellular and humoral anti-tumor immune response. Indeed, the extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs. Moreover, therapy induced a potent antibody response to several key tumor cell surface and secreted proteins; these antibodies manifest functional activity in vitro, antagonizing tumor cell survival, invasive potential, and angiogenesis.
Through an analysis of cytokine deficient mice, we delineated a critical role for GM-CSF in Treg homeostasis. GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity. While blockade of MFG-E8 can enhance therapeutic immunity in the context of cancer vaccines, loss of Treg homeostasis with MFG-E8 deficiency can lead to chronic inflammation. Mice deficient in GM-CSF and IFN-γ develop at high frequency germinal center derived lymphomas and nonsmall cell lung carcinomas. The pathogenesis of these tumors reflects a combination of tumor-promoting inflammation and a loss of protective tumor immunity. Taken together, these findings highlight dual roles for immunity in cancer pathogenesis and therapy.
Citation Format: Glenn Dranoff. The interplay of inflammation and cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA8.
Whole Exome Sequencing Implicates an
INO80D
Mutation in a Syndrome of Aortic Hypoplasia, Premature Atherosclerosis, and Arterial Stiffness
Authors: Shameer Khader , Klee Eric W. , Dalenberg Angela K. , Kullo Iftikhar J. 
Published: August 2014

Background—
Massively parallel, high-throughput sequencing technology is helping to generate new insights into the genetic basis of human diseases. We used whole exome sequencing to identify the mutation underlying a syndrome affecting 2 siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract.

Methods and Results—

Exonic regions were captured and sequenced using a next-generation sequencing platform to generate 100 bases paired-end reads. A computational genomic data analysis pipeline was used to perform quality control, align reads to a reference genome, and identify genetic variants; findings were confirmed using a different exome analyses pipeline. The 2 siblings were homozygous for a rare missense mutation (Ser818Cys) in
INO80D
, a subunit of the human INO80 chromatin remodeling complex. Homozygosity mapping and Sanger sequencing confirmed that the mutation is located in one of the runs of homozygosity on chromosome 2.
INO80D
encodes a key subunit of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding. By introducing a new disulphide-bond in the protein product and also disrupting the composition of low-complexity regions, the Ser818Cys mutation may affect INO80D function, protein–protein interactions, and chromatin remodeling.

Conclusions—

Our findings suggest a link between the Ser818Cys mutation in
INO80D
, a subunit of the human INO80 chromatin remodeling complex, and accelerated arterial aging.
Evaluation of Tropical Cyclone Center Identification Methods in Numerical Models
Authors: Nguyen Leon T. , Molinari John , Thomas Diana 
Published: August 2014

Abstract
Identifying the center of a tropical cyclone in a high-resolution model simulation has a number of operational and research applications, including constructing a track, calculating azimuthal means and perturbations, and diagnosing vortex tilt. This study evaluated several tropical cyclone center identification methods in a high-resolution Weather Research and Forecasting (WRF) Model simulation of a sheared, intensifying, asymmetric tropical cyclone. The simulated tropical cyclone (TC) contained downshear convective cells and a mesovortex embedded in a broader TC vortex, complicating the identification of the TC vortex center. It is shown that unlike other methods, the pressure centroid method consistently 1) placed the TC center within the region of weak storm-relative wind, 2) produced a smooth track, 3) yielded a vortex tilt that varied smoothly in magnitude and direction, and 4) was insensitive to changes in horizontal grid resolution. Based on these results, the authors recommend using the pressure centroid to define the TC center in high-resolution numerical models.
The pressure centroid was calculated within a circular region representing the size of the TC inner core. To determine this area, the authors propose normalizing by the innermost radius at which the azimuthally averaged storm-relative tangential wind at 2-km height equals 80% of the maximum (R80) at 2-km height. Although compositing studies have often normalized by the radius of maximum wind (RMW), R80 proved less sensitive to slight changes in flat tangential wind profiles. This enables R80 to be used as a normalization technique not only with intense TCs having peaked tangential wind profiles, but also with weaker TCs having flatter tangential wind profiles.