ABSTRACT
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.
Subject(s)
Antigens, Neoplasm/immunology , Autoantibodies/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Membrane Proteins/immunology , Ovarian Neoplasms/immunology , Adult , Aged , Aged, 80 and over , Autoantibodies/blood , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Female , Humans , Immunohistochemistry , Lymphocyte Count , Middle AgedABSTRACT
The bovine and ovine TRG genes have previously been shown to be located in two loci, TRG1 and TRG2, in contrast to human and mouse TRG genes that are located in a single locus. The bovine TRG1 and TRG2 loci are located on chromosome 4 at 4q3.1 and 4q1.5-2.2, respectively. The complete genomic organization of the two bovine loci is described: each locus comprises three cassettes, each one includes one or several variable genes (TRGV) and one or several joining genes (TRGJ) preceding a constant (TRGC) gene. The location of the TRGC5 cassette is conclusively described in 5' of the TRG1 locus. Analysis of 17 TRGV belonging to 10 different subgroups, 8 TRGJ and 6 TRGC genes is conducted which comprises the most comprehensive list to date.
Subject(s)
Cattle/genetics , Genes, T-Cell Receptor gamma/genetics , Genome/genetics , Amino Acid Sequence , Animals , Base Sequence , Chromosomes, Artificial, Bacterial/genetics , DNA/chemistry , DNA/genetics , Gene Library , Molecular Sequence Data , Phylogeny , Sequence Alignment , Sequence Analysis, DNAABSTRACT
We report 80,388 ESTs from 23 Atlantic salmon (Salmo salar) cDNA libraries (61,819 ESTs), 6 rainbow trout (Oncorhynchus mykiss) cDNA libraries (14,544 ESTs), 2 chinook salmon (Oncorhynchus tshawytscha) cDNA libraries (1317 ESTs), 2 sockeye salmon (Oncorhynchus nerka) cDNA libraries (1243 ESTs), and 2 lake whitefish (Coregonus clupeaformis) cDNA libraries (1465 ESTs). The majority of these are 3' sequences, allowing discrimination between paralogs arising from a recent genome duplication in the salmonid lineage. Sequence assembly reveals 28,710 different S. salar, 8981 O. mykiss, 1085 O. tshawytscha, 520 O. nerka, and 1176 C. clupeaformis putative transcripts. We annotate the submitted portion of our EST database by molecular function. Higher- and lower-molecular-weight fractions of libraries are shown to contain distinct gene sets, and higher rates of gene discovery are associated with higher-molecular weight libraries. Pyloric caecum library group annotations indicate this organ may function in redox control and as a barrier against systemic uptake of xenobiotics. A microarray is described, containing 7356 salmonid elements representing 3557 different cDNAs. Analyses of cross-species hybridizations to this cDNA microarray indicate that this resource may be used for studies involving all salmonids.
