A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging

Cell. 2018 Sep 6;174(6):1373-1387.e19. doi: 10.1016/j.cell.2018.08.039.

Abstract

The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology.

Keywords: Breast Cancer; Checkpoint; Imaging; MIBI; Mass spectrometry; Multiplexed Ion Beam Imaging; Proteomics; Systems Biology; Tumor Immunology; Tumor Microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, CD / metabolism
  • B7-H1 Antigen / metabolism
  • Cluster Analysis
  • Female
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Kaplan-Meier Estimate
  • Lymphocytes / cytology
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Machine Learning
  • Mass Spectrometry*
  • Principal Component Analysis
  • Programmed Cell Death 1 Receptor / metabolism
  • Spatial Analysis
  • Triple Negative Breast Neoplasms / diagnostic imaging
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology*
  • Tumor Microenvironment / immunology*

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • CD223 antigen
  • CD274 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor