Immune Escape Strategies Research Articles

Cervical intraepithelial neoplasia (CIN) and cervical carcinoma harbour highly increased numbers of Foxp3+ CD4+ CD25+ regulatory T-cells

Active immune suppression by tumors and premalignant lesions supports malignant growth and limits the effect of immune based therapies. Reduction of MHC-mediated antigen presentation or release of immunosuppressive cytokines are common immune escape strategies in cancer, in addition there is a rapidly growing body of evidence that utilization of regulatory T-cells for inactivation of tumor specific cytotoxic T-cells is an accessory widespread and important key mechanism for active immune suppression by cancer. During the last two years several relevant preclinical studies have been published, which show that inactivation of regulatory T-cells substantially enhance the efficacy of immune based therapies. Since there is only limited information about the presence of regulatory T-cells in cervical cancer and its precursors we have compared the amount of Foxp3+ T-cells in cervical cancer, melanoma, colon cancer and lung cancer by immunohistochemistry. We could demonstrate that among these tumors cervical carcinoma harbour the highest numbers of regulatory T-cells. Lymphocyte infiltration is predominantly confined to tumor stroma, where the amount of regulatory T-cells reaches up to 10–20% of all CD3+ lymphocytes. Increased amounts of regulatory T-cells can also be detected in the stroma of cervical neoplastic lesions (CIN). In a mouse model for cervical cancer (TC1 tumors) we demonstrated that inactivation of regulatory T-cells by specific antibodies during the effector phase after therapeutic vaccination (with an HPV E6/E7 specific adenoviral vector) enhances the therapeutic effect of the viral vaccine. These findings suggest that future protocols for immune therapy of cervical cancer and cervical neoplasia should integrate measures for inactivation of regulatory T-cells to improve the cytotoxic strength of tumor specific CD8+ T-cells.

Comparative transcriptional and functional profiling of clear cell and papillary renal cell carcinoma

Renal cell carcinoma (RCC) is known to effectively prevent immune recognition. However, little is known about the mechanisms that underlie this phenomenon. Thus, the identification of immunogenic molecules associated with RCC and the elucidation of the corresponding signaling pathways are crucial to the development of effective treatments. We performed transcriptional and functional profiling with cDNA microarrays (1070 cDNA probes) on a total of 17 RCCs, 11 clear cell and 6 papillary, and on corresponding normal tissue. Samples were clustered based on their expression profiles. We found a total of 45 genes to be regulated equally by both tumor types compared to the normal tissue. A set of 13 differentially expressed genes was identified between the examined tumor subtypes. Functional analysis was performed for both gene sets and showed a significant enrichment of cell surface genes regulated in both tumor subtypes. Within these we found five surface marker genes to be upregulated (TNFRSF10B, CD70, TNFR1, PDGFRB, and BAFF) which are involved in immune responses via the regulation of lymphocytes and can also induce apoptosis. Their overexpression in both tumor subtypes suggests a possible involvement in the immune escape strategies of RCC. The combination of transcriptional and functional profiling revealed potential target molecules for novel therapy strategies that must be studied in more detail.

Low-dose cyclophosphamide modulates galectin-1 expression and function in an experimental rat lymphoma model.

In recent years, one of the most important insights into tumor immunity was provided by the identification of negative regulatory pathways and immune escape strategies that greatly influence the magnitude of antitumor responses. Galectin-1 (Gal-1), a member of a family of highly conserved beta-galactoside-binding proteins, has been recently shown to contribute to tumor cell evasion of immune responses by modulating survival and differentiation of effector T cells. However, there is still scarce information about the regulation of Gal-1 expression and function in vivo. Here we show that administration of a single low-dose cyclophosphamide (Cy), which is capable of restraining metastasis in the rat lymphoma model L-TACB, can also influence Gal-1 expression in primary tumor, metastasis, and spleen cells and modulate the effects of this protein on T cell survival. A time-course study revealed a positive correlation between Gal-1 expression and tumor volume in primary tumor cells. Conversely, Gal-1 expression was significantly reduced in spleen cells and lymph node metastasis throughout the period studied. Interestingly, cyclophosphamide treatment was capable of restoring the basal levels of Gal-1 expression in primary tumors and spleens. In addition, this antimetastatic agent rendered spleen T cells from tumor-bearing animals resistant to Gal-1-induced cell death. Our results suggest that, in addition to other well-known functions of cyclophosphamide, this immunomodulatory agent may also modulate Gal-1 expression and function during tumor growth and metastasis with critical implications for tumor-immune escape and immunotherapy.

An SopB-mediated immune escape mechanism of Salmonella enterica can be subverted to optimize the performance of live attenuated vaccine carrier strains

Salmonellae have evolved several mechanisms to evade host clearance. Here, we describe the influence on bacterial immune escape of the effector protein SopB, which is translocated into the cytosol through a type III secretion system. Wild-type bacteria, as well as the sseC and aroA attenuated mutants exerted a stronger cytotoxic effect on dendritic cells (DC) than their SopB-deficient derivatives. Cells infected with the double sseC sopB, phoP sopB and aroA sopB mutants also exhibited higher expression of MHC, CD80, CD86 and CD54 molecules, and showed a stronger capacity to process and present an I-Ed-restricted epitope from the influenza hemagglutinin (HA) to CD4+ cells from TCR-HA transgenic mice in vitro. The incorporation of an additional mutation into the sopB locus of the attenuated sseC, phoP and aroA mutants resulted in the stimulation of improved humoral and cellular immune responses following oral vaccination. The obtained results define a new potential immune escape strategy of this important pathogen, and also demonstrate that this mechanism can be subverted to optimize the immune responses elicited using Salmonella as a live vaccine carrier.

Alcohol Abuse Enhances Neuroinflammation and Impairs Immune Responses in an Animal Model of Human Immunodeficiency Virus-1 Encephalitis

Neuroinflammatory disorders (including human immunodeficiency virus-1 encephalitis, HIVE) are associated with oxidative stress and inflammatory brain injury, and excessive alcohol use can exacerbate tissue damage. Using a murine model of HIVE, we investigated the effects of alcohol abuse on the clearance of virus-infected macrophages and neuroinflammation. Severe combined immunodeficient mice were reconstituted with human lymphocytes, and encephalitis was induced by intracranial injection of HIV-1-infected monocyte-derived macrophages (HIV-1(+) MDM). Animals were fed an ethanol-containing diet beginning 2 weeks before lymphocyte engraftment and for the entire duration of the experiment. Lymphocyte engraftment was not altered by ethanol exposure. Alcohol-mediated immunosuppression in ethanol-fed mice was manifested by a significant decrease in CD8(+)/interferon-gamma(+) T lymphocytes, a fivefold increase in viremia, and diminished expression of immunoproteasomes in the spleen. Although both groups showed similar amounts of CD8(+) T-lymphocyte infiltration in brain areas containing HIV-1(+) MDMs, ethanol-fed mice featured double the amounts of HIV-1(+) MDMs in the brain compared to controls. Ethanol-exposed mice demonstrated higher microglial reaction and enhanced oxidative stress. Alcohol exposure impaired immune responses (increased viremia, decreased immunoproteasome levels, and prevented efficient elimination of HIV-1(+) MDMs) and enhanced neuroinflammation in HIVE mice. Thus, alcohol abuse could be a co-factor in progression of HIV-1 infection of the brain.

Immunology of hepatitis B virus and hepatitis C virus infection

More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.

Immune escape and exploitation strategies of cytomegaloviruses: impact on and imitation of the major histocompatibility system.

Cytomegalovirus (CMV) has yielded many insights into immune escape mechanisms. Both human and mouse CMV encode a diverse array of gene products, many of which appear to modulate the immune response in the host. Some deflect the host response to infection and contribute to lifelong viral persistence while others exploit immune cells that respond to infection. Here, the viral functions that modulate and mimic host major histocompatibility complex (MHC) function will be reviewed. Viral gene products related to both classical and non-classical components of the MHC system assure the virus will persist in immunocompetent individuals. Examples of host countermeasures that neutralize viral immunomodulatory functions have emerged in the characterization of viral functions that contribute to this stand-off in CMVs that infect humans, other primates and rodents. CMV-induced disease occurs when the immune system is not yet developed, such as in the developing fetus, or when it is compromised, such as in allograft transplant recipients, suggesting that the balance between virus escape and host control is central to pathogenesis. Although evidence supports the dominant role of immune escape in CMV pathogenesis and persistence, MHC-related immunomodulatory functions have been ascribed only subtle impact on pathogenesis and the immune response during natural infection. Viral gene products that interface with the MHC system may impact natural killer cell function, antigen presentation, and T lymphocyte immune surveillance. Many also interact with other cells, particularly those in the myeloid lineage, with consequences that have not been explored. Overall, the virus-encoded modulatory functions that have been acquired by CMV likely ensure survival and adaptation to the wide range of mammalian host species in which they are found.

A comparison of viral immune escape strategies targeting the MHC class I assembly pathway

Peptide fragments from proteins of intracellular pathogens such as viruses are displayed at the cell surface by MHC class I molecules thus enabling surveillance by cytotoxic T cells. Peptides are produced in the cytosol by proteasomal degradation and translocated into the endoplasmic reticulum by the peptide transporter TAP. Empty MHC class I molecules associate with TAP prior to their acquisition of peptides, a process which is assisted and controlled by a series of chaperones. The first part of this review summarizes our current knowledge of this assembly pathway and describes recent observations that tapasin functions as an endoplasmic reticulum retention molecule for empty MHC class I molecules. To defeat the presentation of virus-derived peptides, several DNA viruses have devised strategies to interfere with MHC class I assembly. Although these evasion strategies have evolved independently and differ mechanistically they often target the same step in this pathway. We compare escape mechanisms of different viruses with particular emphasis on the retention of newly synthesized MHC class I molecules in the endoplasmic reticulum and the inhibition of peptide transport by viral proteins.