Mesothelin Expression in Advanced Gastroesophageal Cancer Represents a Novel Target for Immunotherapy - PubMed (original) (raw)

Mesothelin Expression in Advanced Gastroesophageal Cancer Represents a Novel Target for Immunotherapy

Peter B Illei et al. Appl Immunohistochem Mol Morphol. 2016 Apr.

Abstract

The identification of new therapeutic targets is of profound importance if we are to improve outcomes in gastroesophageal cancer. This study assessed the rate of mesothelin expression in tumors of western patients with upper gastrointestinal tract carcinomas. In addition, the AGS gastric cancer cell line was tested for sensitivity to SS1(dsFv)PE38, a mesothelin-targeting immunotoxin. Previously constructed tissue microarrays containing samples from 127 patients with gastroesophageal adenocarcinomas were examined by immunohistochemistry (IHC) for mesothelin expression. Labeling for HER2-neu, E-cadherin, and c-met were also assessed. Tumors were considered positive for mesothelin if at least moderate cytoplasmic/membranous or luminal staining was present in minimum 10% of the neoplastic cells. The AGS gastric cancer cell line was assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Gastroesophageal cancers were mesothelin positive in 64 of 127 tumors [50.4%; 95% confidence interval (CI), 41.4%-59.4%], whereas only 9 carcinomas (7.1%; 95% CI, 3.3%-13.0%) were HER2-neu IHC 3+ positive and 8 (6.6%; 95% CI, 2.9%-12.5%) were c-met positive. Mesothelin expression increased from stage I to stage IV tumors (37.5% to 56.3%, respectively, P=0.10). The AGS gastric cancer cell line was sensitive to the immunotoxin with an EC50 value in the low picomolar range (0.4 ng/mL). A gastric cancer cell line derived from a western patient was exquisitely sensitive to the mesothelin-targeted immunotoxin SS1P. Clinical trials involving novel mesothelin targeted immunotherapeutics in gastroesophageal cancer are currently in development.

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Figures

Figure 1

Figure 1

Representative images of immunohistochemistry for mesothelin, E-cadherin, Her2/Neu and c-met.

Figure 2

Figure 2

FACS analysis of mesothelin surface expression of AGS cells. Live cells were labeled with anti-mesothelin antibody and then antibody was detected with PE-conjugated secondary antibody. A) Representative histogram of PE detection in greater than 20,000 AGS cells (shaded curve) compared to control (unfilled curve). B) WST-8 cell viability assay of SS1P treated AGS cells. 100% viability was normalized to measurement for untreated cells and 0% viability to cells treated with 10 mcg/mL cyclohexamide which produces complete cell death. A representative cytotoxicity curves is shown. Each point represents the average of triplicate measurements. The dotted horizontal line marks 50% cell killing. The vertical arrow indicates the IC50 for the run. The average IC50 after 8 experiments was 0.4 ng/mL.

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