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Involvement of platelet-tumor cell interaction in immune evasion. Potential role of podocalyxin-like protein 1  [PDF]
Laura Amo,Estibaliz Tamayo-Orbegozo,Cristina Eguizabal,Olatz Zenarruzabeitia,Jorge Monge,Miguel A. Vesga,Francisco Borrego,Susana Larrucea
Frontiers in Oncology , 2014, DOI: 10.3389/fonc.2014.00245
Abstract: Besides their essential role in hemostasis and thrombosis, platelets are involved in the onset of cancer metastasis by interacting with tumor cells. Platelets release secretory factors that promote tumor growth, angiogenesis, and metastasis. Furthermore, the formation of platelet-tumor cell aggregates in the bloodstream provides cancer cells with an immune escape mechanism by protecting circulating malignant cells from immune-mediated lysis by natural killer (NK) cells. Platelet-tumor cell interaction is accomplished by specific adhesion molecules, including integrins, selectins, and their ligands. Podocalyxin-like protein 1 (PCLP1) is a selectin ligand protein which overexpression has been associated with several aggressive cancers. PCLP1 expression enhances cell adherence to platelets in an integrin-dependent process and through the interaction with P-selectin expressed on activated platelets. However, the involvement of PCLP1-induced tumor-platelet interaction in tumor immune evasion still remains unexplored. The identification of selectin ligands involved in the interaction of platelets with tumor cells may provide help for the development of effective therapies to restrain cancer cell dissemination. This article summarizes the current knowledge on molecules that participate in platelet-tumor cell interaction as well as discusses the potential role of PCLP1 as a molecule implicated in tumor immune evasion.
T Cell-Tumor Interaction Directs the Development of Immunotherapies in Head and Neck Cancer  [PDF]
A. E. Albers,L. Strauss,T. Liao,T. K. Hoffmann,A. M. Kaufmann
Clinical and Developmental Immunology , 2010, DOI: 10.1155/2010/236378
Abstract: The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy.
Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients  [PDF]
Heriberto Prado-Garcia,Susana Romero-Garcia,Dolores Aguilar-Cazares,Manuel Meneses-Flores,Jose Sullivan Lopez-Gonzalez
Journal of Immunology Research , 2012, DOI: 10.1155/2012/741741
Abstract: Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer. 1. Introduction Lung cancer is the leading cause of cancer-related mortality in developed countries and the second leading cause of death in countries with emerging economies. Worldwide, lung cancer is one of the most commonly diagnosed neoplasias, representing 13% of all cancer cases and approximately 18% of all cancer deaths [1–3]. In countries with emerging economies, the adoption of cancer-associated lifestyles such as reduced physical activity, smoking, unhealthy dietary habits, the increased air pollution, and an aging population has led to a boost in the prevalence of lung cancer [1, 2, 4]. Lung carcinomas are classified as either of two types: small cell lung carcinoma (SCLC) and non-SCLC (NSCLC). NSCLC accounts for approximately 85% of all lung cancer cases and includes three histological subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Treatment of NSCLC involves surgery in the early stages, chemotherapy with concurrent radiation for some locally advanced cancers, and palliative chemotherapy for metastatic disease. In developing countries, most lung cancer diagnoses are performed at advanced stages of lung malignancy and therefore 5-year survival rates remain low [4,
Comparison of T-cell receptor repertoire restriction in blood and tumor tissue of colorectal cancer patients
Sebastian Ochsenreither, Alberto Fusi, Susanne Wojtke, Antonia Busse, Natascha C Nüssler, Eckhard Thiel, Ulrich Keilholz, Dirk Nagorsen
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-35
Abstract: Understanding the interaction between tumor and immune system might help improving immunotherapeutic approaches for malignant diseases. T-cells directed against tumor associated antigens (TAA) could play a key role in the surveillance of and in the defense against tumor cells [1]. In fact, spontaneous T-cell responses against TAAs have been described in peripheral blood, lymph nodes, and bone marrow of patients with various malignant diseases prior to immunotherapy [2].In colorectal cancer (CRC), spontaneous T-cell responses against several TAAs have been detected in peripheral blood, particularly in patients with metastatic disease [3,4]. No evidence was found that these spontaneous, peripheral TAA-specific T-cells have an impact on survival of CRC patients [5]. Therefore, the focus of interest has moved to tumor-infiltrating T cells. CD8+ T-cell infiltration of CRC is known to be associated with a better prognosis, but it is still unknown whether these infiltrating T cells, in fact, represent expanded tumor specific T-cell clones [6-13].In case of unknown or multiple epitopes, the analysis of TCR repertoire both by FACS and PCR based methods offers the opportunity to detect oligoclonal expansion of specific T-cells [14-16]. The dimeric transmembrane T-cell receptor (TCR) is the central mediator of epitope specific cytotoxic T-cell activation. Consisting of an α- and a β-chain in most of the cases, diversity is generated during T-cell evolution by recombinations of the gene segments V (variable), in case of the β-chain D (diversity), and J (joining) to a constant chain gene C [17]. V-genes are grouped in families consisting of genes with sequence homology of at least 50% [18]. For analysis of the TCR repertoire, the β-chain is often preferred because of the lower number of families even if a higher overall variability of sequence compared to the α-chain has been described [19]. Alterations in TCR repertoire can be evaluated either by length or sequence analysis of
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.
T Cell-Tumor Interaction Directs the Development of Immunotherapies in Head and Neck Cancer  [PDF]
A. E. Albers,L. Strauss,T. Liao,T. K. Hoffmann,A. M. Kaufmann
Journal of Immunology Research , 2010, DOI: 10.1155/2010/236378
Abstract: The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy. 1. Introduction Squamous cell carcinomas of the head and neck (SCCHN) are the sixth most frequent type of malignancy worldwide. SCCHN accounts for approximately 6% of all cancer cases and for about 650,000 new cases and 350,000 deaths worldwide each year [1–3]. While early-stage SCCHN can be treated relatively effectively, fewer than 40% of patients with advanced, metastatic disease can be cured. Unfortunately, about two thirds of patients with SCCHN present with advanced-stage disease, commonly involving regional lymph nodes. Distant metastases are found in about 10% of patients at initial presentation. The 5-year survival for all stages is about 60%. Despite significant improvements in surgery, radiation, and chemotherapy, long-term survival rates in patients with advanced stage SCCHN have not significantly increased in the past 30 years [4–6]. Mortality from SCCHN remains high because of the development of distant metastases and the emergence of therapy-resistant local and regional recurrences. It is therefore essential to develop a deeper understanding of the biology of this disease for more effective alternative therapies such as immunotherapy. As basis for immunotherapeutic approaches, interactions between tumors and the host immune system have been a subject of many studies. It has been shown that a naturally induced T-cell response recognizing SCCHN exists that could potentially target and possibly kill the tumor cells. Most cases in which this may have happened will
How the Virus Outsmarts the Host: Function and Structure of Cytomegalovirus MHC-I-Like Molecules in the Evasion of Natural Killer Cell Surveillance
Maria Jamela Revilleza,Rui Wang,Janet Mans,Manqing Hong,Kannan Natarajan,David H. Margulies
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/724607
Abstract: Natural killer (NK) cells provide an initial host immune response to infection by many viral pathogens. Consequently, the viruses have evolved mechanisms to attenuate the host response, leading to improved viral fitness. One mechanism employed by members of the β-herpesvirus family, which includes the cytomegaloviruses, is to modulate the expression of cell surface ligands recognized by NK cell activation molecules. A novel set of cytomegalovirus (CMV) genes, exemplified by the mouse m145 family, encode molecules that have structural and functional features similar to those of host major histocompatibility-encoded (MHC) class I molecules, some of which are known to contribute to immune evasion. In this review, we explore the function, structure, and evolution of MHC-I-like molecules of the CMVs and speculate on the dynamic development of novel immunoevasive functions based on the MHC-I protein fold.
Gamma-Herpesvirus Latency Requires T Cell Evasion during Episome Maintenance  [PDF]
Neil J. Bennett,Janet S. May,Philip G. Stevenson
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0030120
Abstract: The gamma-herpesviruses persist as latent episomes in a dynamic lymphocyte pool. Their consequent need to express a viral episome maintenance protein presents a potential immune target. The glycine–alanine repeat of the Epstein–Barr virus episome maintenance protein, EBNA-1, limits EBNA-1 epitope presentation to CD8+ T lymphocytes (CTLs). However, CTL recognition occurs in vitro, so the significance of such evasion for viral fitness is unclear. We used the murine gamma-herpesvirus-68 (MHV-68) to define the in vivo contribution of cis-acting CTL evasion to host colonisation. Although the ORF73 episome maintenance protein of MHV-68 lacks a glycine–alanine repeat, it was equivalent to EBNA-1 in conferring limited presentation on linked epitopes. This was associated with reduced protein synthesis and reduced protein degradation. We bypassed the cis-acting evasion of ORF73 by using an internal ribosome entry site to express in trans-a CTL target from the same mRNA. This led to a severe, MHC class I–restricted and CTL-dependent reduction in viral latency. Thus, despite MHV-68 encoding at least two trans-acting CTL evasion proteins, cis-acting evasion during episome maintenance was essential for normal host colonisation.
Gamma-Herpesvirus Latency Requires T Cell Evasion during Episome Maintenance
Bennett Neil J,May Janet S,Stevenson Philip G
PLOS Biology , 2005, DOI: 10.1371/journal.pbio.0030120.20050521
Abstract: The gamma-herpesviruses persist as latent episomes in a dynamic lymphocyte pool. Their consequent need to express a viral episome maintenance protein presents a potential immune target. The glycine-alanine repeat of the Epstein-Barr virus episome maintenance protein, EBNA-1, limits EBNA-1 epitope presentation to CD8+ T lymphocytes (CTLs). However, CTL recognition occurs in vitro, so the significance of such evasion for viral fitness is unclear. We used the murine gamma-herpesvirus-68 (MHV-68) to define the in vivo contribution of cis-acting CTL evasion to host colonisation. Although the ORF73 episome maintenance protein of MHV-68 lacks a glycine-alanine repeat, it was equivalent to EBNA-1 in conferring limited presentation on linked epitopes. This was associated with reduced protein synthesis and reduced protein degradation. We bypassed the cis-acting evasion of ORF73 by using an internal ribosome entry site to express in trans-a CTL target from the same mRNA. This led to a severe, MHC class I-restricted and CTL-dependent reduction in viral latency. Thus, despite MHV-68 encoding at least two trans-acting CTL evasion proteins, cis-acting evasion during episome maintenance was essential for normal host colonisation.
Gamma-Herpesvirus Latency Requires T Cell Evasion during Episome Maintenance  [PDF]
Neil J Bennett,Janet S May,Philip G Stevenson
PLOS Biology , 2005, DOI: 10.1371/journal.pbio.0030120
Abstract: The gamma-herpesviruses persist as latent episomes in a dynamic lymphocyte pool. Their consequent need to express a viral episome maintenance protein presents a potential immune target. The glycine–alanine repeat of the Epstein–Barr virus episome maintenance protein, EBNA-1, limits EBNA-1 epitope presentation to CD8+ T lymphocytes (CTLs). However, CTL recognition occurs in vitro, so the significance of such evasion for viral fitness is unclear. We used the murine gamma-herpesvirus-68 (MHV-68) to define the in vivo contribution of cis-acting CTL evasion to host colonisation. Although the ORF73 episome maintenance protein of MHV-68 lacks a glycine–alanine repeat, it was equivalent to EBNA-1 in conferring limited presentation on linked epitopes. This was associated with reduced protein synthesis and reduced protein degradation. We bypassed the cis-acting evasion of ORF73 by using an internal ribosome entry site to express in trans-a CTL target from the same mRNA. This led to a severe, MHC class I–restricted and CTL-dependent reduction in viral latency. Thus, despite MHV-68 encoding at least two trans-acting CTL evasion proteins, cis-acting evasion during episome maintenance was essential for normal host colonisation.
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