Humoral immune response to MUC5AC in patients with colorectal polyps and colorectal carcinoma

BACKGROUND: MUC5AC is a secreted mucin aberrantly expressed by colorectal polyps and carcinoma. It has been hypothesized that aberrant expression of MUC5AC in colorectal carcinoma tissues increased the overall survival of patients with colorectal carcinoma. The present study investigates the incidence of naturally occurring MUC5AC antibodies in the sera of normal individuals, patients with colonic polyps and patients with advanced colorectal carcinoma. A second aim was to determine the relationship of MUC5AC antibody with the prognosis of colorectal carcinoma. METHODS: Free circulating MUC5AC antibodies were measured using an enzyme-linked immunosorbent assay with a synthetic peptide corresponding to an 8 aa. segment of MUC5AC tandem repeat region. Immunohistochemical analysis was completed to demonstrate MUC5AC expression in the polyp specimens. RESULTS: MUC5AC antibodies were detected in 6 of 22 (27.3%) healthy subjects, 9 of 20 (45%) polyp patients, 18 of 30 (60%) patients with colorectal cancer. The presence of circulating free MUC5AC antibody levels was significantly correlated with expression of MUC5AC in polyp sections. Serum MUC5AC antibody positivity was higher in patients with colon located tumors, advanced stage and poorly differentiated tumors were found negatively affecting patient survival in our study. MUC5AC antibody positivity was higher in patients with poor prognostic parameters. Disease free survival and overall survival were shorter in this group of patients. In the multivariate analysis MUC5AC antibody positivity didn't find an independent prognostic factor on prognosis. CONCLUSION: Decreased survival in colorectal carcinoma patients with MUC5AC antibody positivity may be due to a decrease in the MUC5AC expression in tumor tissues of surviving carcinoma patients

Tumor-Infiltrating T Cells Correlate with NY-ESO-1-Specific Autoantibodies in Ovarian Cancer

BACKGROUND: Tumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens. METHODOLOGY AND PRINCIPAL FINDINGS: We obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-gamma ELISPOT and MHC class I pentamer staining. CONCLUSION AND SIGNIFICANCE: We demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy

Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835]

INTRODUCTION: Mucin 1 (MUC1) is a high molecular weight glycoprotein overexpressed on adenocarcinoma cells and is a target for immunotherapy protocols. To date, clinical trials against MUC1 have included advanced cancer patients. Herein, we report a trial using early stage breast cancer patients and injection of oxidized mannan-MUC1. METHOD: In a randomized, double-blind study, 31 patients with stage II breast cancer and with no evidence of disease received subcutaneous injections of either placebo or oxidized mannan-MUC1, to immunize against MUC1 and prevent cancer reoccurrence/metastases. Twenty-eight patients received the full course of injections of either oxidized mannan-MUC1 or placebo. Survival and immunological assays were assessed. RESULTS: After more than 5.5 years had elapsed since the last patient began treatment (8.5 years from the start of treatment of the first patient), the recurrence rate in patients receiving the placebo was 27% (4/15; the expected rate of recurrence in stage II breast cancer); those receiving immunotherapy had no recurrences (0/16), and this finding was statistically significant (P = 0.0292). Of the patients receiving oxidized mannan-MUC1, nine out of 13 had measurable antibodies to MUC1 and four out of 10 had MUC1-specific T cell responses; none of the placebo-treated patients exhibited an immune response to MUC1. CONCLUSION: The results suggest that, in early breast cancer, MUC1 immunotherapy is beneficial, and that a larger phase III study should be undertaken