Malignant mesothelioma-associated antigens recognized by tumor-infiltrating B cells and the clinical significance of the antibody titers.
ABSTRACT Malignant pleural mesothelioma (MPM) is difficult to diagnose at an early stage. The present study attempted to obtain a tumor-specific antibody against MPM derived from tumor-infiltrating B lymphocytes in MPM by using a xenotransplanted severe combined immunodeficiency (SCID) mouse model, and to identify the antigens recognized by the antibodies. Among the antigen-antibody relationships, the clinical usefulness of antibody titers in the sera was evaluated from the viewpoint of diagnosis of MPM and monitoring of therapeutic effects. Tumor tissue specimens from two patients with MPM were engrafted subcutaneously in SCID mice and blood samples were obtained and pooled every 2 weeks after xenotransplantation until 14 weeks when the mice were killed. A cDNA library was constructed from the mRNA of a MPM cell line (K921MSO). Immunoscreening of the libraries was carried out by serological identification of antigens by a recombinant expression cloning method (SEREX) and four antigens were identified as MPM-associated antigens. Among them, antibody titers against two antigens, Gene-X and thrombospondin-2 (THBS-2), were analyzed by phage plaque assay as the first step. ELISA systems correlated with the phage plaque assay to detect antibody titers against the two antigens were constructed using 20-mer peptides of the antigen-coding genes. The cut-off value was decided by the average and standard deviation of normal healthy persons. Antibody against Gene-X was detected in 10 out of 18 (55.6%) mesothelioma patients and antibody against THBS-2 was detected in 16 out of 18 (88.9%) mesothelioma patients. No patients with lung cancer regardless of asbestos exposure exhibited positive antibody titer against the two antigens. Furthermore, the serum antibody titers decreased after surgical treatment of MPM and increased after recurrence of the disease. The titers of the antibodies against Gene-X and THBS-2 could be used as tumor markers for the diagnosis and follow up of patients with MPM.
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ABSTRACT: This study aims to determine whether a semi-quantitative assessment of inflammatory response in tumor and stroma on routine hematoxylin and eosin-stained (H&E) slides can predict survival in patients with epithelioid malignant pleural mesothelioma (MPM). H&E sections of 175 epithelioid MPM specimens from a single institution (1989-2009) were reviewed. Patients who received neoadjuvant chemotherapy were excluded from analysis. Each tumor was histologically assessed for acute and chronic inflammatory response both within the tumor and the stromal component. Inflammatory response was graded: low (none to mild infiltrate) or high (moderate to severe infiltrate). Log-rank test and Cox proportional hazards regression were used to investigate the association between the degree of inflammation (acute/tumor, acute/stroma, chronic/tumor, and chronic/stroma) and overall survival (OS). Patients with high chronic inflammatory response in stroma (n = 59) had improved survival compared to low (n = 116) (median OS = 19.4 vs. 15.0 months, P = 0.01). This prognostic stratification remained significant in stage III patients (median OS = 16.0 vs. 9.3 months, P = 0.03). In multivariate analysis, chronic inflammation in stroma was an independent predictor of survival (HR = 0.659, 95% CI 0.464-0.937, P = 0.02). While high degree of chronic inflammatory cell infiltration in the stromal component was associated with improved overall survival, degree of other inflammatory responses did not show significant correlation with OS. Our study for the first time investigates inflammatory response in tumor and stroma and not only suggests the prognostic value of inflammatory response in epithelioid MPM but also provides rationale for investigation of immunotherapy to benefit epithelioid MPM patients.Cancer Immunology and Immunotherapy 07/2011; 60(12):1721-8. · 3.64 Impact Factor
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ABSTRACT: Hyaluronic acid (HA) has been proposed as a biochemical marker of malignant pleural mesothelioma (MPM). The present study focused on the implications of HA and CD44 interaction in the proliferation and invasiveness of MPM. The proliferation and invasive activity was evaluated in two human mesothelioma cell lines, ACC-MESO-1 and K921MSO, by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the transwell chamber model. The knockdown of CD44 gene expression was accomplished by transfection of the cells with small interfering RNA. Flow cytometry revealed that both the ACC-MESO-1 and K921MSO cell lines highly expressed CD44. Treatment with HA enhanced the proliferation in both mesothelioma cell lines in comparison to cells without HA treatment. The treatment with HA (25 μg/ml) also significantly upregulated the invasion of both types of cells. The silencing of CD44 significantly abrogated the effect of HA treatment on the proliferation of ACC-MESO-1 cells and significantly suppressed the proliferation of K921MSO cells. HA-CD44 binding is important for the migration and proliferation of mesothelioma cells. Therefore, the HA-CD44 interaction is a potentially useful therapeutic target in MPM.Tumor Biology 08/2012; · 2.52 Impact Factor
Chapter: B Lymphocytes in Cancer Immunology[show abstract] [hide abstract]
ABSTRACT: The role of B lymphocytes in the pathogenesis and treatment of cancer has not received as much attention as the role of T cells. However, most patients with solid tumors harbor circulating antitumor antibodies and most tumors contain a population of infiltrating B cells implying an association between oncogenic events and B-cell activation. B-cell immunity can be beneficial by providing antibody-mediated protection from oncogenic viruses or a source of recombinant tumor-specific antibodies that can be used in combination with chemotherapeutic regimens. However, activation of B cells may also be detrimental to an effective antitumor response. Tumor-reactive antibodies and B cells often recognize antigens that are generated during the unscheduled apoptotic and necrotic death processes, which accompany tumor progression and may be involved in wound-healing processes that promote tumor growth and impair protective T-cell responses. Therefore, methods to eliminate autoreactive B cells, or switch them to a B effector-1 (Be-1) phenotype that amplifies Th1/Tc1-type T-cell responses, which are typically associated with effective antitumor responses, may improve the clinical outcomes of T-cell-mediated immunotherapies. Possible strategies include the administration of B-cell-depleting monoclonal antibodies, use of targeted B-cell stimulatory agents such as Toll-like Receptor agonists, and adoptive transfer of large numbers of ex vivo generated tumor-reactive Be-1 cells. KeywordsB lymphocytes-Cancer vaccines-Chronic lymphocytic leukemia-Regulatory B cells-Tumor immunology12/2010: pages 37-57;