Spontaneous immune responses against glioma-associated antigens in a long term survivor with malignant glioma

<p>Abstract</p> <p>Background</p> <p>In patients with high grade glioma, little is known regarding existence of naturally occurring adaptive T cell reactivity against glioma-associated antigens (GAAs). In this report, we characterized GAA-specific CD8⁺T cells and innate immune cells in a patient who has survived with anaplastic astrocytoma (AA) for over 12 years without recurrence.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells (PBMCs) derived from the long term survivor with AA were evaluated for the frequency, cytotoxic T lymphocyte (CTL) activity and differentiation status of CD8⁺cells recognizing GAA-derived epitopes as well as relative numbers of other immune cell subsets. This patient's AA tissue was evaluated for expression of two GAAs EphA2 and interleukin-13 receptor α2 subunit (IL-13Rα2) by immunohistochemistry.</p> <p>Results</p> <p>The patient's tumor expressed both EphA2 and IL-13Rα2, and <it>in vitro </it>stimulated PBMC demonstrated superior EphA2_883–891and IL-13Rα2_345–353-specific CTL reactivity compared to PBMC samples from two other patients with progressing malignant glioma. Unstimulated EphA2_883–891-reactive CD8⁺T cells contained high numbers of CD45RA^-/CCR7^-late effector and CD45RA^-/CCR7⁺central memory cells. Among other leukocyte subsets, elevated numbers of NK-T cells were found.</p> <p>Conclusion</p> <p>To our knowledge, the current study is one of the first demonstrating the presence of antigen-experienced, GAA-reactive CD8⁺T cells in a patient who has survived with AA for over 12 years without recurrence. Further studies are warranted to determine whether the status of GAA-reactive CD8⁺T cells dictates survival of patients and/or response to therapeutic vaccines.</p

Differential activity of interferon-α8 promoter is regulated by Oct-1 and a SNP that dictates prognosis of glioma

We have previously reported that the single nucleotide polymorphism (SNP) rs12553612 in IFNA8 is associated with better overall survival of glioma patients with the AA-genotype compared with patients with the AC-genotype. As rs12553612 is located in the IFNA8 promoter, we hypothesized that the A-allele allows for an enhanced IFNA8 promoter activity compared with the C-allele. Reporter assays in the human monocyte derived THP-1 cell line demonstrated a superior promoter activity of the A-allele compared with the C-allele. Electrophoretic mobility shift assays (EMSA) further demonstrated that the A-genotype specifically binds to more nuclear proteins than the C-genotype, including the transcription factor Oct-1. Further, co-transfection of plasmids encoding Oct-1 and the reporter constructs revealed that Oct-1 enhanced the promoter activity with the A- but not the C-allele. Taken together, our data demonstrate that the A-allele in the rs12553612 SNP, which is associated with better glioma patient survival, allows for IFNA8 transcription by allowing for Oct-1 binding, which is absent in patients with C allele, and suggests a molecular mechanism of IFNA8 mediated immune-surveillance of glioma progression

Malignant Peritoneal Mesothelioma Mimicking Ischemic Colitis

The prognosis of malignant peritoneal mesothelioma is extremely poor with a mean survival time of 12 months. The initial symptoms are poor and atypical. Because of its rare entity and little knowledge of its treatments, there are few reports of long-term survival. We encountered a very unique case with strong impression on radiological findings of malignant peritoneal methothelioma. We had misdiagnosed it because of the findings and because the time course was similar to that of ischemic colitis. The radiological findings on CT and enema disappeared within one week after antibiotic therapy

Job stress factors measured by Brief Job Stress Questionnaire and sickness absence among Japanese workers: A longitudinal study

This study aimed to investigate associations between Brief Job Stress Questionnaire (BJSQ)-measured job stress factors and sickness absence in Japanese workers. Among 551 healthy, employed Japanese men and women (age range: 21-73 years) who underwent mental health examinations at the Osaka Medical Center for Health Science and Promotion between 2006 and 2009, 197 (67 men, 130 women) consented to participate in this study. Their sickness absences until the end of March 2010 were then followed-up via postal mail survey, with 112 participants effectively responding to the question on sickness absence (56.9%). The hazard ratio (HR) and 95% confidence interval (CI) were calculated using the Cox proportional hazards model, adjusting for age, sex, and lifestyle factors. Among the 112 respondents, 12 took sickness absence after their study entry, as found during the mean 2.3 years of follow-up (258.8 person-years). Among all sickness absences, those of eight participants were because of mental illness. Physical demands were positively associated with increased risks of all sickness absence (adjusted HR: 2.78, 95% CI: 1.01-7.64). Physical demands were predictive for all sickness absence, and should be alleviated at workplaces to prevent such absence

Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models

BACKGROUND: Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations. METHODS: C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC. RESULTS: The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity. CONCLUSION: These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy

miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy

<p>Abstract</p> <p>Background</p> <p>Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated.</p> <p>Methods</p> <p>We performed miR microarray analyses on <it>in vitro </it>differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells.</p> <p>Results</p> <p>Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4⁺T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD).</p> <p>Conclusion</p> <p>The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.</p