Topological Tumor Graphs: A Graph-Based Spatial Model to Infer Stromal Recruitment for Immunosuppression in Melanoma Histology.
Abstract
Despite the advent of immunotherapy, metastatic melanoma represents an aggressive tumor type with a poor survival outcome. The successful application of immunotherapy requires in-depth understanding of the biological basis and immunosuppressive mechanisms within the tumor microenvironment. In this study, we conducted spatially explicit analyses of the stromal-immune interface across 400 melanoma hematoxylin and eosin (H&E) specimens from The Cancer Genome Atlas. A computational pathology pipeline (CRImage) was used to classify cells in the H&E specimen into stromal, immune, or cancer cells. The estimated proportions of these cell types were validated by independent measures of tumor purity, pathologists' estimate of lymphocyte density, imputed immune cell subtypes, and pathway analyses. Spatial interactions between these cell types were computed using a graph-based algorithm (topological tumor graphs, TTG). This approach identified two stromal features, namely stromal clustering and stromal barrier, which represented the melanoma stromal microenvironment. Tumors with increased stromal clustering and barrier were associated with reduced intratumoral lymphocyte distribution and poor overall survival independent of existing prognostic factors. To explore the genomic basis of these TTG-derived stromal phenotypes, we used a deep learning approach integrating genomic (copy number) and transcriptomic data, thereby inferring a compressed representation of copy number-driven alterations in gene expression. This integrative analysis revealed that tumors with high stromal clustering and barrier had reduced expression of pathways involved in naïve CD4 signaling, MAPK, and PI3K signaling. Taken together, our findings support the immunosuppressive role of stromal cells and T-cell exclusion within the vicinity of melanoma cells. SIGNIFICANCE: Computational histology-based stromal phenotypes within the tumor microenvironment are significantly associated with prognosis and immune exclusion in melanoma.
Collections
Subject
T-Lymphocytes
Lymphocytes, Tumor-Infiltrating
Stromal Cells
Skin
Humans
Melanoma
Skin Neoplasms
Image Interpretation, Computer-Assisted
Biopsy
Prognosis
Cohort Studies
Follow-Up Studies
Tumor Escape
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Models, Biological
Adult
Aged
Aged, 80 and over
Middle Aged
DNA Copy Number Variations
Kaplan-Meier Estimate
Tumor Microenvironment
Spatial Analysis
Biomarkers, Tumor
Antineoplastic Agents, Immunological
Deep Learning
RNA-Seq
Research team
Computational Pathology & Integrated Genomics
Language
eng
Date accepted
2019-12-10
License start date
2020-03
Citation
Cancer research, 2020, 80 (5), pp. 1199 - 1209
Publisher
AMER ASSOC CANCER RESEARCH
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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