Fingerprinting the circulating repertoire of antibodies from cancer patients

Abstract

Recognition of molecular diversity in disease is required for the development of targeted therapies. We have developed a screening method based on phage display to select peptides recognized by the repertoire of circulating tumor-associated antibodies. Here we isolated peptides recognized by antibodies purified from the serum of prostate cancer patients. We identified a consensus motif, NX(S/T)DK(S/T), that bound selectively to circulating antibodies from cancer patients over control antibodies from blood donors. We validated this motif by showing that positive serum reactivity to the peptide was specifically linked to disease progression and to shorter survival in a large patient population. Moreover, we identified the corresponding protein eliciting the immune response. Finally, we showed a strong and specific positive correlation between serum reactivity to the tumor antigen, development of metastatic androgen-independent disease, and shorter overall survival. Exploiting the differential humoral response to cancer through such an approach may identify molecular markers and targets for diagnostic and therapeutic intervention.

Cloning of B cell lymphoma-associated antigens using modified phage-displayed expression cDNA library and immunized patient sera

“…6A). Out of frame peptides are known to be cloned when antibodydisplayed phage library were used by others (Mintz et al, 2003;Wang et al, 2005). The U1-snRNP 70K is a common target for autoantibodies in lupus and scleroderma-spectrum disorders, including mixed connective tissue disease (St Clair et al, 1990).…”

An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment

“…Upon binding, the ␤ 1 integrin changes conformation from a bent to extended (active) form and thereby triggers downstream phosphorylation of target proteins in the integrinmediated pathway (steps 3 and 4) and/or MAPK pathway (steps 5-7), affecting tumor cell migration and proliferation (step 8). Precedent for intracellular molecules such as nuclear proteins (40,41), transcription factors (42), and stress-response chaperones (13,43,44) on the cell surface has been reported. Ligand-receptor interactions between signaling molecules and surface receptors within the extracellular environment may have general biological significance.…”

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

“…␣B-crystallin, another heat shock protein implicated in resistance to cell death in various cancer types, is also regulated by LEDGF/ p75 (88,106), but to our knowledge the presence of autoantibodies to this protein in prostate cancer sera has not been reported. Another stress response protein, glucose-regulated protein-78 kDa (GRP78), was shown to be a target of autoantibodies in advanced prostate cancer but not in lung, breast, and ovarian cancers (108). Overexpression of this protein was detected in metastatic prostate cancer but not in normal prostate (108).…”

“…Another stress response protein, glucose-regulated protein-78 kDa (GRP78), was shown to be a target of autoantibodies in advanced prostate cancer but not in lung, breast, and ovarian cancers (108). Overexpression of this protein was detected in metastatic prostate cancer but not in normal prostate (108). We have also demonstrated the presence of serum autoantibodies in prostate cancer patients against p62, Koc, and IMP1, proteins that bind the mRNA of IGF-II, an important global regulator of cell survival in breast and prostate cancers (109 -111).…”