1,720,985 research outputs found
Genetic Variants as Targets for Immunotherapy of Hematological Tumors
No full textThis eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contac
Tuning the show: Genetic engineering to unravel antigen presentation by the human leukocyte antigen class I
Get PDFThe HLA-I antigen presentation pathway is indispensable for T cell mediated tumor destruction. Disruption of this pathway is a key process for tumor immune escape. In this thesis, we sought to identify novel mechanisms of known and previously unknown factors in the antigen presentation pathway, with the ultimate goal to define targeted strategies to improve CD8+ T cell based anti-tumor therapy. We first describe the generation and validation of PAKC, a panel of ten human cell lines from a single genetic background. Each cell line is made knockout for a gene involved in the antigen presentation pathway using CRISPR/Cas9. Due to their identical background, these cell lines are ideal for comparative studies on the influence of each of the knocked-out factors. Using PAKC, we identified an antigen presented independently of TAP on both healthy and TAP-deficient cells. Our results emphasize the need for extensive testing to define clinically relevant antigens to safely target TAP-deficient tumors. Finally, a genome-wide haploid screening on HLA-I identified that the protease SPPL3 positively regulates accessibility of HLA-I for various of its ligands by inhibition of neolacto-series GSL (nsGSL) synthesis. Reactivity of CD8+ T cells towards cells overexpressing nsGSLs was decreased compared to cells lacking nsGSLs. Analysis of the TCGA glioma cohort revealed that there is a negative association between nsGSL synthesis genes and patient survival. Our data indicate that tumors can evade immunity through expression of nsGSLs
Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment
Get PDFThe molecular identification of tumor antigens initially catalyzed substantial enthusiasm for the development of tumor antigen-based vaccines for the treatment of cancer. However, numerous vaccine approaches in melanoma and other cancers have yielded a low rate of clinical response, despite frequent induction of specific T cells as detected in the peripheral blood. This observation has prompted several investigators to begin interrogating the tumor microenvironment for biologic correlates to tumor response versus resistance. Evidence is beginning to emerge suggesting that distinct subsets of tumors may exist that reflect distinct categories of immune escape. Lack of chemokine-mediated trafficking, poor innate immune cell activation, and the presence of specific immune suppressive mechanisms can be found to characterize subsets of tumors. A non-inflamed tumor phenotype may predict for resistance to cancer vaccines, suggesting a possible predictive biomarker and patient enrichment strategy. But in addition, characterization of these subsets may pave the way for catering therapeutic interventions toward the biologic features of the tumor in individual patients.Fil: Gajewski, Thomas F.. University Of Chicago; Estados UnidosFil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. University Of Chicago; Estados UnidosFil: Spaapen, Robbert. University Of Chicago; Estados UnidosFil: Zheng, Yan. University Of Chicago; Estados UnidosFil: Kline, Justin. University Of Chicago; Estados Unido
Mediators of intercellular communication in immune responses
Get PDFThe immune system is in charge of clearing the human body of pathogens and tumor cells to prevent, resolve or mitigate disease. To fulfill this task it employs many different cell types with unique capabilities, as each threat requires a different strategy to ensure clearance. Intercellular communication is of vital importance to activate or inhibit the appropriate (immune) cells at the right moment. Cells can communicate with each other through direct cell-cell contact or remotely through secretion of soluble signaling molecules. These soluble molecules include secreted proteins that can be recognized by other cells if they express the right receptors. We developed a library of human secreted proteins for use in several high-throughput screens to identify additional secreted proteins that affect specific immune responses. This approach led to the identification of fibroblast growth factors as a class of viral replication inhibitors, soluble FAS ligand as an inducer of memory B cell differentiation into antibody secreting cells, and IL-21 an inducer of granzyme B expression in activated CD4+ T cells. In addition, the research in this thesis describes that tumor infiltrating lymphocytes (TILs) derived from renal cell carcinoma cannot make sufficient cytokines when co-cultured with autologous tumor digest, a type of secreted proteins, after in vitro expansion. In conclusion, this thesis revealed additional roles of known secreted proteins that support intercellular communication during immune responses, thereby expanding our knowledge of immunological communication
Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature
No full textEndogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-β, and conditional deletion of IFN-α/βR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.Fil: Spaapen, Robbert . University Of Chicago; Estados UnidosFil: Leung, Michael Y. K.. University Of Chicago; Estados UnidosFil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. University Of Chicago; Estados UnidosFil: Kline, Justin P.. University Of Chicago; Estados UnidosFil: Zhang, Long . University Of Chicago; Estados UnidosFil: Zheng, Yan . University Of Chicago; Estados UnidosFil: Fu, Yang Xin. University Of Chicago; Estados UnidosFil: Luo, Xixi . University Of Chicago; Estados UnidosFil: Cohen, Kenneth S. . University Of Chicago; Estados UnidosFil: Gajewski, Thomas F. . University Of Chicago; Estados Unido
The Connection Between Minor H Antigens and Neoantigens and the Missing Link in Their Prediction
No full textFor hundreds of thousands of years, the human genome has extensively evolved, resulting in genetic variations in almost every gene. Immunological reflections of these genetic variations become clearly visible after an allogeneic stem cell transplantation (allo-SCT) as minor Histocompatibility (H) antigens. Minor H antigens are peptides cleaved from genetically encoded variable protein regions after which they are presented at the cell surface by HLA molecules. After allo-SCT with minor H antigen mismatches between donor and recipient, donor T cells recognize the minor H antigens of the recipient as foreign, evoking strong alloreactive immune responses. Studies in the late eighties have discovered that a subset of minor H antigens are encoded by hematopoietic system-specific genes. After allo-SCT, this subset is strictly expressed on the hematopoietic malignant cells and was therefore the first well-defined highly immunogenic group of tumor-specific antigens. In the last decade, neoantigens derived from genetic mutations in tumors have been identified as another group of immunogenic tumor-specific antigens. Therefore, hematopoietic minor H antigens and neoantigens are therapeutic equivalents. This review will connect our current knowledge about the immune biology and identification of minor H antigens and neoantigens leading to novel conclusions on their prediction
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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