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The role of the microenvironment in tumor immune surveillance  [cached]
Oluwadayo Oluwadara,Luca Giacomelli,Xenia Brant,Russell Christensen4
Bioinformation , 2011,
Abstract: The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O’Shea & Paul, 2010 ). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.
Bridging Innate and Adaptive Antitumor Immunity Targeting Glycans
Anastas Pashov,Bejatolah Monzavi-Karbassi,Gajendra P. S. Raghava,Thomas Kieber-Emmons
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/354068
Abstract: Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC) in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the “altered self” hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies.
Tumor-Associated Glycans and Their Role in Gynecological Cancers: Accelerating Translational Research by Novel High-Throughput Approaches  [PDF]
Tatiana Pochechueva,Francis Jacob,Andre Fedier,Viola Heinzelmann-Schwarz
Metabolites , 2012, DOI: 10.3390/metabo2040913
Abstract: Glycans are important partners in many biological processes, including carcinogenesis. The rapidly developing field of functional glycomics becomes one of the frontiers of biology and biomedicine. Aberrant glycosylation of proteins and lipids occurs commonly during malignant transformation and leads to the expression of specific tumor-associated glycans. The appearance of aberrant glycans on carcinoma cells is typically associated with grade, invasion, metastasis and overall poor prognosis. Cancer-associated carbohydrates are mostly located on the surface of cancer cells and are therefore potential diagnostic biomarkers. Currently, there is increasing interest in cancer-associated aberrant glycosylation, with growing numbers of characteristic cancer targets being detected every day. Breast and ovarian cancer are the most common and lethal malignancies in women, respectively, and potential glycan biomarkers hold promise for early detection and targeted therapies. However, the acceleration of research and comprehensive multi-target investigation of cancer-specific glycans could only be successfully achieved with the help of a combination of novel high-throughput glycomic approaches.
Glycan Elongation Beyond the Mucin Associated Tn Antigen Protects Tumor Cells from Immune-Mediated Killing  [PDF]
Caroline B. Madsen, Kirstine Lavrsen, Catharina Steentoft, Malene B. Vester-Christensen, Henrik Clausen, Hans H. Wandall, Anders Elm Pedersen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072413
Abstract: Membrane bound mucins are up-regulated and aberrantly glycosylated during malignant transformation in many cancer cells. This results in a negatively charged glycoprotein coat which may protect cancer cells from immune surveillance. However, only limited data have so far demonstrated the critical steps in glycan elongation that make aberrantly glycosylated mucins affect the interaction between cancer cells and cytotoxic effector cells of the immune system. Tn (GalNAc-Ser/Thr), STn (NeuAcα2-6GalNAc-Ser/Thr), T (Galβ1–3GalNAc-Ser/Thr), and ST (NeuAcα2-6Galβ1–3GalNAc-Ser/Thr) antigens are recognized as cancer associated truncated glycans, and are expressed in many adenocarcinomas, e.g. breast- and pancreatic cancer cells. To investigate the role of the cancer associated glycan truncations in immune-mediated killing we created glyco-engineered breast- and pancreatic cancer cells expressing only the shortest possible mucin-like glycans (Tn and STn). Glyco-engineering was performed by zinc finger nuclease (ZFN) knockout (KO) of the Core 1 enzyme chaperone COSMC, thereby preventing glycan elongation beyond the initial GalNAc residue in O-linked glycans. We find that COSMC KO in the breast and pancreatic cancer cell lines T47D and Capan-1 increases sensitivity to both NK cell mediated antibody-dependent cellular-cytotoxicity (ADCC) and cytotoxic T lymphocyte (CTL)-mediated killing. In addition, we investigated the association between total cell surface expression of MUC1/MUC16 and NK or CTL mediated killing, and observed an inverse correlation between MUC16/MUC1 expression and the sensitivity to ADCC and CTL-mediated killing. Together, these data suggest that up-regulation of membrane bound mucins protects cells from immune mediated killing, and that particular glycosylation steps, as demonstrated for glycan elongation beyond Tn and STn, can be important for fine tuning of the immune escape mechanisms in cancer cells.
The growth dynamics of tumor subject to both immune surveillance and external therapy intervention
YuanZhi Shao,WeiRong Zhong,FengHua Wang,ZhenHui He,ZhongJun Xia
Chinese Science Bulletin , 2007, DOI: 10.1007/s11434-007-0234-9
Abstract: Considering the growth of tumor cells modeled by an enzyme dynamic process under an immune surveillance, we studied in anti-tumor immunotherapy the single-variable growth dynamics of tumor cells subject to a multiplicative noise and an external therapy intervention simultaneously. The law of tumor growth of the above anti-tumor immunotherapy model was revealed through numerical simulations to the relevant stochastic dynamic differential equation. Two simulative parameters of therapy, i.e., therapy intensity and therapy duty-cycle, were introduced to characterize a treatment process similar to a tumor clinic therapy. There exists a critical therapy boundary which, in an exponent-decaying form, divides the parameter region of therapy into an invalid and a valid treatment zone, respectively. A greater critical therapy duty-cycle is necessary to achieve a valid treatment for a lower therapy intensity while the critical therapy intensity decreases accordingly with an enhancing immunity. A primary clinic observation of the patients with the typical non-hodgekin’s lymphoma was carried out, and there appears a basic agreement between clinic observations and dynamic simulations.
The growth dynamics of tumor subject to both immune surveillance and external therapy intervention
SHAO YuanZhi,ZHONG WeiRong,WANG FengHua,HE ZhenHui,XIA ZhongJun,
SHAO
,YuanZhi,ZHONG,WeiRong,WANG,FengHua,HE,ZhenHui,XIA,ZhongJun

科学通报(英文版) , 2007,
Abstract: Considering the growth of tumor cells modeled by an enzyme dynamic process under an immune surveillance, we studied in anti-tumor immunotherapy the single-variable growth dynamics of tumor cells subject to a multiplicative noise and an external therapy intervention simultaneously. The law of tumor growth of the above anti-tumor immunotherapy model was revealed through numerical simulations to the relevant stochastic dynamic differential equation. Two simulative parameters of therapy, i.e., therapy intensity and therapy duty-cycle, were introduced to characterize a treatment process similar to a tumor clinic therapy. There exists a critical therapy boundary which, in an exponent-decaying form, divides the parameter region of therapy into an invalid and a valid treatment zone, respectively. A greater critical therapy duty-cycle is necessary to achieve a valid treatment for a lower therapy intensity while the critical therapy intensity decreases accordingly with an enhancing immunity. A primary clinic observation of the patients with the typical non-hodgekin’s lymphoma was carried out, and there appears a basic agreement between clinic observations and dynamic simulations. Supported by the National Natural Science Foundation of China (Grant No. 60471023)
Ectonucleotidases in Tumor Cells and Tumor-Associated Immune Cells: An Overview
Letícia Scussel Bergamin,Elizandra Braganhol,Rafael Fernandes Zanin,Maria Isabel Albano Edelweiss,Ana Maria Oliveira Battastini
Journal of Biomedicine and Biotechnology , 2012, DOI: 10.1155/2012/959848
Abstract: Increasing evidence points out that genetic alteration does not guarantee the development of a tumor and indicates that complex interactions of tumor cells with the microenvironment are fundamental to tumorigenesis. Among the pathological alterations that give tumor cells invasive potential, disruption of inflammatory response and the purinergic signaling are emerging as an important component of cancer progression. Nucleotide/nucleoside receptor-mediated cell communication is orchestrated by ectonucleotidases, which efficiently hydrolyze ATP, ADP, and AMP to adenosine. ATP can act as danger signaling whereas adenosine, acts as a negative feedback mechanism to limit inflammation. Many tumors exhibit alterations in ATP-metabolizing enzymes, which may contribute to the pathological events observed in solid cancer. In this paper, the main changes occurring in the expression and activity of ectonucleotidases in tumor cells as well as in tumor-associated immune cells are discussed. Furthermore, we focus on the understanding of the purinergic signaling primarily as exemplified by research done by the group on gliomas.
Spatiotemporal Fluctuation Induced Transition in a Tumor Model with Immune Surveillance  [PDF]
Wei-Rong Zhong,Yuan-Zhi Shao,Zhen-Hui He
Physics , 2006, DOI: 10.1103/PhysRevE.74.011916
Abstract: We report on a simple model of spatial extend anti-tumor system with a fluctuation in growth rate, which can undergo a nonequilibrium phase transition. Three states as excited, sub-excited and non-excited states of a tumor are defined to describe its growth. The multiplicative noise is found to be double-face: The positive effect on a non-excited tumor and the negative effect on an excited tumor.
Spatiotemporal Noise Triggering Infiltrative Tumor Growth under Immune Surveillance  [PDF]
Wei-Rong Zhong,Yuan-Zhi Shao,Li Li,Feng-Hua Wang,Zhen-Hui He
Quantitative Biology , 2008, DOI: 10.1209/0295-5075/82/20003
Abstract: A spatiotemporal noise is assumed to reflect the environmental fluctuation in a spatially extended tumor system. We introduce firstly the structure factor to reveal the invasive tumor growth quantitatively. The homogenous environment can lead to an expansive growth of the tumor cells, while the inhomogenous environment underlies an infiltrative growth. The different responses of above two cases are separated by a characteristic critical intensity of the spatiotemporal noise. Theoretical and numerical results present a close annotation to the clinical images.
Engagement of the Mannose Receptor by Tumoral Mucins Activates an Immune Suppressive Phenotype in Human Tumor-Associated Macrophages  [PDF]
P. Allavena,M. Chieppa,G. Bianchi,G. Solinas,M. Fabbri,G. Laskarin,A. Mantovani
Journal of Immunology Research , 2010, DOI: 10.1155/2010/547179
Abstract: Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype. 1. Introduction Among tumor-infiltrating leukocytes, Tumor-Associated Macrophages (TAMs) constitute a major subset [1–3]. While the presence of T lymphocytes in tumor stroma is usually correlated with more favourable prognosis of cancer patients [4, 5], in most studies the density of TAM is associated with rapid tumor progression [6–9]. TAMs are poorly cytotoxic against neoplastic cells and may actually favour tumor cell survival and proliferation by actively producing growth factors for cancer and endothelial cells. They are also a major source of proteolytic enzymes that degrade the extra-cellular matrix thus favouring the invasion of neoplastic cells [9, 10]. Further, TAM contributes to the evasion of tumors from immune control by producing immune-suppressive cytokines such as IL-10 and TGFβ [2, 9]. Our group proposed that TAMs are M2-like polarized macrophages [11]. Along a conventional definition, macrophages activated in the presence of inflammatory mediators (e.g., LPS) and Th1 cytokines (e.g., IFNγ) are defined as M1 or classically activated macrophages. These effectors have high cytotoxic functions, produce immune-stimulatory cytokines, and are important cells for the defense against intracellular pathogens and transformed cells [11–13]. On the other hand M2
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