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Multiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry.

ΤίτλοςMultiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry.
Publication TypeJournal Article
Year of Publication2019
AuthorsCarvajal-Hausdorf, D. E., Patsenker J., Stanton K. P., Villarroel-Espindola F., Esch A., Montgomery R. R., Psyrri A., Kalogeras K. T., Kotoula V., Foutzilas G., Schalper K. A., Kluger Y., & Rimm D. L.
JournalClin Cancer Res
Volume25
Issue10
Pagination3054-3062
Date Published2019 05 15
ISSN1078-0432
Λέξεις κλειδιάAdult, Antineoplastic Agents, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, Cohort Studies, Female, Humans, Image Cytometry, Lymphocytes, Tumor-Infiltrating, Neoplasm Recurrence, Local, Signal Transduction, T-Lymphocytes, Cytotoxic, Trastuzumab
Abstract

PURPOSE: Imaging mass cytometry (IMC) uses metal-conjugated antibodies to provide multidimensional, objective measurement of protein targets. We used this high-throughput platform to perform an 18-plex assessment of HER2 ICD/ECD, cytotoxic T-cell infiltration and other structural and signaling proteins in a cohort of patients treated with trastuzumab to discover associations with trastuzumab benefit.
EXPERIMENTAL DESIGN: An antibody panel for detection of 18 targets (pan-cytokeratin, HER2 ICD, HER2 ECD, CD8, vimentin, cytokeratin 7, β-catenin, HER3, MET, EGFR, ERK 1-2, MEK 1-2, PTEN, PI3K p110 α, Akt, mTOR, Ki67, and Histone H3) was used with a selection of trastuzumab-treated patients from the Hellenic Cooperative Oncology Group 10/05 trial ( = 180), and identified a case-control series.
RESULTS: Patients that recurred after adjuvant treatment with trastuzumab trended toward a decreased fraction of HER2 ECD pixels over threshold compared with cases without recurrence ( = 0.057). After exclusion of the lowest HER2 expressers, 5-year recurrence events were associated with reduced total extracellular domain (ECD)/intracellular domain (ICD) ratio intensity in tumor ( = 0.044). These observations are consistent with our previous work using quantitative immunofluorescence, but represent the proof on identical cell content. We also describe the association of the ECD of HER2 with CD8 T-cell infiltration on the same slide.
CONCLUSIONS: The proximity of CD8 cells as a function of the expression of the ECD of HER2 provides further evidence for the role of the immune system in the mechanism of action of trastuzumab.

DOI10.1158/1078-0432.CCR-18-2599
Alternate JournalClin Cancer Res
PubMed ID30796036
PubMed Central IDPMC6522272
Grant ListR01 GM131642 / GM / NIGMS NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
R01 HG008383 / HG / NHGRI NIH HHS / United States
R01 CA139431 / CA / NCI NIH HHS / United States
P30 CA016359 / CA / NCI NIH HHS / United States

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