Cell
Volume 173, Issue 7, 14 June 2018, Pages 1755-1769.e22
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Article
Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer

https://doi.org/10.1016/j.cell.2018.03.073Get rights and content
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Highlights

  • Immune infiltrates vary across space within patients at the time of diagnosis

  • Immune infiltration shapes malignant cell evolutionary trajectories

  • T cell clones track with tumor clones across spatial sites within patients

  • Immune infiltrates and mutational processes show prognostic interactions

Summary

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.

Keywords

high-grade serous ovarian cancer
HGSC
intratumoral heterogeneity
tumor-infiltrating lymphocyte
foldback inversion
immunoediting
metastatic
clone
mutation signature
clonal evolution
human leukocyte antigen
HLA

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17

These authors contributed equally

18

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