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Results for “Immune Escape”

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PubMed2006

Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer.

Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen-specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression. However, the mechanism(s) responsible for the lack of tumor cell recognition by functional HLA class I antigen-restricted, tumor antigen-specific CTLs despite expression of the restricting HLA class I allele and targeted tumor antigen by tumor cells remain(s) unexplained. In squamous cell carcinomas of the head and neck (SCCHN), this type of tumor escape is a rule rather than the exception. Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen-restricted, tumor antigen-specific CTL. In addition, based on the restoration by IFN-gamma of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.

Antigen Presentation↗
PubMed2002

Immune escape through C-type lectins on dendritic cells.

Dendritic cells (DCs) detect different pathogens and elicit tailored anti-microbial immune responses. They express C-type lectins that recognise carbohydrate profiles on microorganisms, resulting in internalisation, processing and presentation. Intracellular sequences of distinct DC-specific lectins point to differences in intracellular routing that influence antigen presentation. Moreover, putative signalling motifs hint to the activation of DCs on carbohydrate recognition. Recent evidence shows that not only pathogens, but also tumour antigens, exploit C-type lectins to escape intracellular degradation resulting in abortive immunity. More insight into ligand specificity, intracellular targeting and signalling will reveal the pathways by which pathogens modulate immunity through C-type lectins.

Animals↗
PubMed2006

A target on the move: innate and adaptive immune escape strategies of hepatitis C virus.

Obligate intracellular parasites such as the hepatitis C virus (HCV) have to cope intensively with immune responses in order to establish persistent infection. Powerful antiviral mechanisms of the host act on several levels. The innate immune response is able to slow down viral replication and activate cytokines which trigger the synthesis of antiviral proteins. The adaptive immune system neutralizes virus particles and destroys infected cells. Viruses have therefore developed a number of countermeasures to stay moving targets for the immune system. Here, we attempt to summarize the current state of research regarding innate and adaptive immune responses against HCV and the different escape strategies evolved by this virus.

Hepacivirus↗
PubMed2004

Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child.

The emergence of cytotoxic T-lymphocyte (CTL) escape mutations in human immunodeficiency virus type 1 (HIV-1) proteins has been anecdotally associated with progression to AIDS, but it has been difficult to determine whether viral mutation is the cause or the result of increased viral replication. Here we describe a perinatally HIV-infected child who maintained a plasma viral load of <400 copies/ml for almost a decade until a nonbinding escape mutation emerged within the immunodominant CTL epitope. The child subsequently experienced a reemergence of HIV-1 viremia accompanied by a marked increase in the number of CTL epitopes targeted. This temporal pattern suggests that CD8 escape can play a causal role in the loss of immune control.

Amino Acid Sequence↗
PubMed2004

[Chronic hepatitis C infection--mechanisms of virus "immune escape"].

The characteristic feature of HCV infection is the presence of both humoral and cellular immune response. In spite of the immune activation the host is unable to eradicate the virus. Spontaneous resolution of chronic infection is exceedingly rare--it is estimated at 0.6% per year. The currently available combination therapies with alpha interferon and ribavirin are effective in limited groups of patients. Factors involved in the mechanism(s) whereby HCV establishes and maintains its persistence are not well understood. The high genetic variability of HCV allows the virus to passively evade the immune system. Data obtained from experiments with cell culture expressing HCV proteins suggest that viral persistency is a multifactorial mechanism. Several viral genes impair cellular functions involved in immune responses.

Antibody Formation↗
PubMed2003

Supernatants from human cytomegalovirus (HCMV)-infected retinal glial cells increase transepithelial electrical resistance in a cell culture model: evidence of HCMV immune escape in the eye?

The underlying mechanisms leading to persistence of human cytomegalovirus (HCMV) in the immune privileged retina are not fully understood. This in vitro study was done to evaluate the influence of HCMV-infected retinal glial cells on epithelial barrier functions. Glial cells derived from human eyes were cultured and infected with the clinical HCMV isolate Hi91. Supernatants of mock (GS(mock)) and Hi91 (GS(Hi91)) -infected glial cells were collected at 72 h post inoculation and used for incubation of CaCo-2 cells grown in transwell chambers. Transepithelial electrical resistance (TER) was analyzed as a measure of epithelial integrity. Virus-free GS(Hi91 )but not GS(mock) increased TER from 250 Omega/cm(2) to more than 1,000 Omega/cm(2)within 2 h. Increased TER values were measured up to 48 h (n = 3). No changes in TER were observed when conditioned supernatants from HCMV-infected human foreskin fibroblasts were used. No evidence of GS(Hi91)-induced modification of beta-catenin (zonula adherens) or occludin and ZO-1 (zonula occludens) was found. Our results suggest that HCMV-infected glial cells may support epithelial barrier functions by a yet unknown mechanism. Our findings may help to explain the ocular persistence of HCMV and the maintenance of ocular immune privilege early in infection.

Blood-Retinal Barrier↗
PubMed2001

A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death.

The immune system attempts to prevent or limit tumor growth, yet efforts to induce responses to tumors yield minimal results, rendering tumors virtually invisible to the immune system [1]. Several mechanisms may account for this subversion, including the triggering of tolerance to tumor antigens [2, 3], TGF-alpha or IL-10 production, downregulation of MHC molecules, or upregulation of FasL expression [4, 5]. Melanoma cells may in some instances use FasL expression to protect themselves against tumor-infiltrating lymphocytes (TIL) [4, 5]. Here, we show another, chemokine-dependent mechanism by which melanoma tumor cells shield themselves from immune reactions. Melanoma-inducible CCL5 (RANTES) production by infiltrating CD8 cells activates an apoptotic pathway in TIL involving cytochrome c release into the cytosol and activation of caspase-9 and -3. This process, triggered by CCL5 binding to CCR5, is not mediated by TNFalpha, Fas, or caspase-8. The effect is not unique to CCL5, as other CCR5 ligands such as CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) also trigger TIL cell death, nor is it limited to melanoma cells, as it also operates in activated primary T lymphocytes. The model assigns a role to the CXC chemokine CXCL12 (SDF-1alpha) in this process, as this melanoma cell-produced chemokine upregulates CCL5 production by TIL, initiating TIL cell death.

Apoptosis↗
PubMedDate not supplied

Constitutive expression of TGF-bêta1, interleukin-6 and interleukin-8 by tumor cells as a major component of immune escape in human ovarian carcinoma.

Tumors could use several mechanisms to coexist with the host's immune system or to protect themselves from an immune response. Thus, insufficient expression of cell surface molecules on tumor cells, which are important for T cell recognition or activation, could lead to induction of a state of tolerance. Tumor cells could also produce cytokines that would inhibit the immune response and allow tumor progression. Here, we studied, in vitro, the cell surface expression of immunologically important molecules in seven ovarian carcinoma (OVCA) cell lines and the constitutive expression of cytokines. All OVCA cell lines expressed MHC class I molecules, ICAM-1 and LFA-3 adhesion molecules, necessary to induce a specific cytotoxic T-cell response, as well as the CD40 costimulatory molecules. Conversely, the lack of the dominant costimulatory molecules, CD80 (B7.1) and CD86 (B7.2) could be a possible explanation of poor immunogenicity of OVCA tumors. Immunosuppressive TGF-beta1 was detected at the mRNA level in all cell lines but was weakly secreted in supernatants. By contrast, IL-10 was never found. Most of them constitutively produced IL-8 and IL-6, two cytokines known as tumor promoting factors whereas the proinflammatory cytokines TNF-alpha, IL-1beta and GM-CSF were rarely produced. Data from this study could be useful for designing new strategies of immunotherapy to improve immunogenicity and/or limit protumor cytokine production.

Biomarkers↗
PubMed2026

Elevated Triggering Receptor Expressed on Myeloid Cells 2 Expression in Tumor-Associated Macrophages Suppresses Cytotoxic T Cell Infiltration and Facilitates Immune Escape in Colorectal Cancer.

BACKGROUND & AIMS: Emerging evidence supports a crucial role for tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment. Furthermore, research has identified that the triggering receptor expressed on myeloid cells 2 has immunomodulatory functions. The present investigated the potential effect of triggering receptor expressed on myeloid cells 2 expression in tumor-associated macrophages on facilitating immune evasion in colorectal cancer. METHODS: Immunohistochemical analysis of clinical specimens, complemented by extensive data mining from The Cancer Genome Atlas, revealed a significant upregulation of triggering receptor expressed on myeloid cells 2 in colorectal cancer-associated tumor-associated macrophages, with this upregulation exhibiting a correlation with poor patient prognosis. RESULTS: Mechanistically, triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages were found to drive fibroblast activation through transforming growth factor-&#x3b2; signaling, inducing fibroblast-activated protein-positive cancer-associated fibroblasts that secrete collagen I/III to establish dense peritumoral barriers. Spatial profiling revealed that these fibrous structures physically impede CD8+ T-cell infiltration, restricting cytotoxic lymphocytes to stromal compartments. Intriguingly, triggering receptor expressed on myeloid cells 2 deficiency enhanced the secretion of matrix metalloproteinase 13 by macrophages, thereby promoting extracellular matrix degradation and improving T-cell penetration. In vivo, Trem2-knockout mice showed a reduction in tumor growth with enhanced intratumoral CD8+ T-cell infiltration compared with wild-type controls. CONCLUSIONS: Our findings establish triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages as central regulators of stromal remodeling and suggest that therapeutic targeting of the triggering receptor expressed on myeloid cells 2/transforming growth factor-&#x3b2;/fibroblast-activated protein pathway may overcome immune resistance in patients with colorectal cancer.

Colorectal Neoplasms↗
PubMed2001

Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator.

Antibacterial peptides are active defense components of innate immunity. Several studies confirm their importance at epithelial surfaces as immediate barrier effectors in preventing infection. Here we report that early in Shigella spp. infections, expression of the antibacterial peptides LL-37 and human beta-defensin-1 is reduced or turned off. The downregulation is detected in biopsies from patients with bacillary dysenteries and in Shigella- infected cell cultures of epithelial and monocyte origin. This downregulation of immediate defense effectors might promote bacterial adherence and invasion into host epithelium and could be an important virulence parameter. Analyses of bacterial molecules causing the downregulation indicate Shigella plasmid DNA as one mediator.

Adult↗
PubMed2001

Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape.

Characteristics of human malignant glioma are excessive proliferation, infiltrative growth, angiogenesis and suppression of anti-tumor immune surveillance. Transforming growth factor-beta (TGF-beta), a versatile cytokine, is intimately involved in the regulation of these processes. Here, we discuss the interactions of TGF-beta with growth factors, such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet derived growth factor (PDGF), metalloproteinases (MMP-2, MMP-9) and their inhibitor, plasmin activator inhibitor-1 (PAI-1), and immune cells, like natural killer cells, T-cells and microglia. The differential effects of TGF-beta in glioma biology are outlined with emphasis on the induction of a survival advantage for glioma cells by enforced cell growth, migration, invasion, angiogenesis and immune paralysis. By virtue of its growth regulatory and immunomodulatory properties, TGF-beta promises to become a novel target for the experimental therapy of human malignant glioma.

Brain Neoplasms↗
PubMed1993

Molecular mechanisms used by tumors to escape immune recognition: immunogenetherapy and the cell biology of major histocompatibility complex class I.

In this article, we explore the hypothesis that tumor cells can escape recognition by CD8+ T cells via deficiencies in antigen processing and presentation. Aspects of the molecular and cellular biology of major histocompatibility complex class I are reviewed. Evidence for histology-specific molecular mechanisms in the antigen-processing and -presentation deficiencies observed in some human and murine tumors is presented. Mechanisms identified include down-regulation of antigen processing, loss of functional beta 2-microglobulin, and deletion of specific alpha-chain alleles. Finally, we discuss studies using an antigen-presentation-deficient mouse tumor as a model for the immunogenetherapy of an antigen-presentation deficiency.

Animals↗
PubMed2004

Immunobiological characterization of N -nitrosomethylurea-induced rat breast carcinomas: tumoral IL-10 expression as a possible immune escape mechanism.

Improvement of immunotherapy-based protocols in cancer requires a better understanding of tumor microenvironment and tumor-host interaction. Stromal and immune cells and molecules such as cytokines, chemokines, growth factors and metalloproteases mediate tumor-host interaction determining, at least in part, tumor development. In the present study, we used an immunohistochemical approach to explore leukocyte sub-populations, cytokine profiles and costimulatory molecule expression in rat N -Nitrosomethylurea (NMU)-induced breast tumors. Our results show a strong leukocyte infiltration mainly composed of macrophages and TCR alphabeta positive T cells. We observed a weak expression of costimulatory molecules (CD80, CD86) and an absence of inflammatory cytokines (IFNgamma, TNFalpha, IP-10) and lymphocyte activation markers (CD25). Interestingly, this immunosuppressed status could be a consequence of IL-10 expression by malignant cells, as demonstrated by immunohistology and western blot analysis, which seems to be an early event during mammary carcinogenesis. Analysis of a cell line derived from an NMU-induced rat breast tumor showed that this cell line also expresses IL-10. This study shows that the NMU model of rat breast cancer could be used to evaluate different immune based therapies as well as to study the role of IL-10 in breast cancer. Furthermore, this rat breast cancer model shows an immunohistological profile similar to that found in human cancer and the fact that it develops like spontaneously arising malignancies make it interesting as a cancer model in immunobiology.

Animals↗
PubMed2002

Immune escape mechanisms of childhood ALL and a potential countering role for DC-like leukemia cells.

BACKGROUND: Pre-B ALL cells generally elicit a weak immune host response, due to poor expression of co-stimulatory molecules and/or suppression of immune function. A possible way to enhance immunogenicity of pre-B ALL cells is to convert them to DC-like cells. METHODS: To study the effect of ALL cells on T-cell function, ALL cells were incubated with T adult cells activated by OKT3 MAb. Liquid culture of de novo pre-B ALL cells for 7 days, in a medium containing IL-1alpha, IL-3, IL-7, Flt 3 ligand (L) and tumor-necrosis factor alpha (TNF-alpha) produced DC-like cells. These were evaluated for morphology, viability, phenotype, as measured by flow cytometry, and function, including MLR. RESULTS: Pre-B ALL cell-lines NALM-6, BALM and de novo pre-B ALL cells failed to stimulate T cells, but suppressed stimulated T cells. The DC-like cells displayed characteristic features of DCs: filiform cytoplasmic projections, and phenotypic expression of co-stimulatory molecules CD80/86, MHC Class I and II molecules, CD83 and CD1a. Genetic monoclonality study confirmed their leukemic origin. In a 5-day MLR culture, the DC-like cells potently activated allogeneic adult and cord CD4+ and CD8+ T cells. Furthermore, both CD4+ and CD8+ T cells were primed towards a Type I. No such effect was seen with unmanipulated de novo pre-B ALL cells. DISCUSSION: DC-like cells can be generated from childhood pre-B ALL cells and are potent stimulators of adult and naïve cord CD8+ T cells via CD4+ cells. These cells may form part of an immunotherapy strategy to overcome tolerance to ALL cells.

B-Lymphocytes↗
PubMed2026

Oncogene SETDB1's dual role: driving tumor progression and immune escape.

Oncogene SETDB1, an H3K9 methyltransferase, drives tumorigenesis in various cancers. Using endometrial cancer (EC) as a model, we discovered SETDB1's dual mechanisms in driving EC tumorigenesis and mediating immune evasion. SETDB1 knockout (SETDB1-/-) tumor-bearing mice exhibited prolonged survival up to 100 days. Transcriptomic profiling of SETDB1-/- EC cells revealed decreased oncogene expression and increased tumor suppressor gene expression, which indicates that SETDB1 intrinsically promotes EC proliferation by regulating these downstream genes. SETDB1 repressed repeat elements and the interferon pathway, mediating immune evasion extrinsically by inhibiting anti-tumor macrophage infiltration. ChIP-seq analysis showed SETDB1 binding at pericentromeric regions on many chromosomes and numerous ZNFs. Loss of SETDB1 resulted in abnormal cell division. SETDB1-/- tumors displayed reduced proliferation markers (Ki67, pHH3) and increased macrophage infiltration. Mechanistically, SETDB1 promotes CD47 (a don't-eat-me signal) and represses CCL5 and CXCL9 (macrophage and T-cell recruiting chemokines), contributing to immune evasion. M1-like macrophages killed more SETDB1-/- cells in co-culture. Additionally, SETDB1 knockout in mouse EC cells reduced tumor growth in C57BL/6 mice, with increased macrophage and CD4&#x2009;+&#x2009;T-cell infiltration. Our results indicate that elevated SETDB1 and its targets can predict higher tumor grade and worse survival, suggesting that targeting SETDB1 could be a promising therapeutic strategy for EC.

Animals↗
PubMed2006

Tumor immune escape mechanisms: impact of the neuroendocrine system.

Tumor cells act upon, and react to both their proximate and more distant environment, the mechanisms by which this is achieved being both autocrine and paracrine in nature. This interaction, however, takes place not only between adjacent malignant cells, but also non-malignant cells such as those of the immune system, the latter also partaking in the modeling of the tumor environment. Although tumor cells descend from normal tissue cells and thus bear in classical immunological terms 'self signals', it is evident that the immune system is able to recognize tumor cells as a harassment for the body and in consequence tries to eliminate these cells. On the counterpart, tumor cells acquire various characteristics which allow them to evade this immunological surveillance, and have been collectively coined with the term "tumor escape mechanisms". This review will describe and summarize current understanding of tumor escape strategies, and also more closely elaborate on the modulatory role of the neuroendocrine system in the immune system-tumor cell interaction.

Animals↗