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The Antibody Repertoire of Colorectal Cancer.

ABSTRACT: Immunotherapy is becoming increasingly important in the fight against cancers, using and manipulating the body's immune response to treat tumors. Understanding the immune repertoire-the collection of immunological proteins-of treated and untreated cells is possible at the genomic, but technically difficult at the protein level. Standard protein databases do not include the highly divergent sequences of somatic rearranged immunoglobulin genes, and may lead to miss identifications in a mass spectrometry search. We introduce a novel proteogenomic approach, AbScan, to identify these highly variable antibody peptides, by developing a customized antibody database construction method using RNA-seq reads aligned to immunoglobulin (Ig) genes.AbScan starts by filtering transcript (RNA-seq) reads that match the template for Ig genes. The retained reads are used to construct a repertoire graph using the "split" de Bruijn graph: a graph structure that improves on the standard de Bruijn graph to capture the high diversity of Ig genes in a compact manner. AbScan corrects for sequencing errors, and converts the graph to a format suitable for searching with MS/MS search tools. We used AbScan to create an antibody database from 90 RNA-seq colorectal tumor samples. Next, we used proteogenomic analysis to search MS/MS spectra of matched colorectal samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) against the AbScan generated database. AbScan identified 1,940 distinct antibody peptides. Correlating with previously identified Single Amino-Acid Variants (SAAVs) in the tumor samples, we identified 163 pairs (antibody peptide, SAAV) with significant cooccurrence pattern in the 90 samples. The presence of coexpressed antibody and mutated peptides was correlated with survival time of the individuals. Our results suggest that AbScan (https://github.com/csw407/AbScan.git) is an effective tool for a proteomic exploration of the immune response in cancers.

SUBMITTER: Cha SW

PROVIDER: S-EPMC5724175 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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The Antibody Repertoire of Colorectal Cancer.

Cha Seong Won SW Bonissone Stefano S Na Seungjin S Pevzner Pavel A PA Bafna Vineet V

Molecular & cellular proteomics : MCP 20171018 12

Immunotherapy is becoming increasingly important in the fight against cancers, using and manipulating the body's immune response to treat tumors. Understanding the immune repertoire-the collection of immunological proteins-of treated and untreated cells is possible at the genomic, but technically difficult at the protein level. Standard protein databases do not include the highly divergent sequences of somatic rearranged immunoglobulin genes, and may lead to miss identifications in a mass spectr ...[more]

PMID: 29046389

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Project description:Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI).We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG.Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33.Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.

Dataset Information

The Antibody Repertoire of Colorectal Cancer.

Publications

The Antibody Repertoire of Colorectal Cancer.

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