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Clin Cancer Res. 2019 Jun 12. doi: 10.1158/1078-0432.CCR-19-0104. [Epub ahead of print]

High-Plex Predictive Marker Discovery for Melanoma Immunotherapy-Treated Patients Using Digital Spatial Profiling.

Author information

1
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
2
NanoString Technologies, Seattle, Washington.
3
Brigham and Women's Hospital, Department of Medicine, Boston, Massachusetts.
4
Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
5
3rd Department of Medicine, University of Athens, School of Medicine, Sotiria General Hospital, Athens, Greece.
6
Department of Pathology, Yale School of Medicine, New Haven, Connecticut. david.rimm@yale.edu.

Abstract

Purpose: Protein expression in formalin-fixed, paraffin-embedded tissue is routinely measured by IHC or quantitative fluorescence (QIF) on a handful of markers on a single section. Digital spatial profiling (DSP) allows spatially informed simultaneous assessment of multiple biomarkers. Here we demonstrate the DSP technology using a 44-plex antibody cocktail to find protein expression that could potentially be used to predict response to immune therapy in melanoma.Experimental Design: The NanoString GeoMx DSP technology is compared with automated QIF (AQUA) for immune marker compartment-specific measurement and prognostic value in non-small cell lung cancer (NSCLC). Then we use this tool to search for novel predictive markers in a cohort of 60 patients with immunotherapy-treated melanoma on a tissue microarray using a 44-plex immune marker panel measured in three compartments (macrophage, leukocyte, and melanocyte) generating 132 quantitative variables.Results: The spatially informed variable assessment by DSP validates by both regression and variable prognostication compared with QIF for stromal CD3, CD4, CD8, CD20, and PD-L1 in NSCLC. From the 132 variables, 11 and 15 immune markers were associated with prolonged progression-free survival (PFS) and overall survival (OS). Notably, we find PD-L1 expression in CD68-positive cells (macrophages) and not in tumor cells was a predictive marker for PFS, OS, and response.Conclusions: DSP technology shows high concordance with QIF and validates based on both regression and outcome assessment. Using the high-plex capacity, we found a series of expression patterns associated with outcome, including that the expression of PD-L1 in macrophages is associated with response.

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