A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging
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.
Additional Information
© 2018 Elsevier Inc. Received 16 April 2018, Revised 13 June 2018, Accepted 17 August 2018, Available online 6 September 2018. The authors thank Tom Carver, Dana Pe'er, Tyler Risom, David Glass, Erin McCaffrey, and Felix Hartmann for discussions and comments. L.K. is supported by the Damon Runyon Cancer Research Foundation (DRG-2292-17) and EMBO Long-Term fellowship (ALTF 1128-2016). D.V.V. is supported by an NIH F32 Postdoctoral Fellowship, a Burroughs Wellcome PDEP award, The Allen Discovery Center at Stanford University, and a Crowdflower A.I. for everyone award. R.W. is supported by NIH5R01CA18390402. S.C.B. is supported by a gift from Christy and Bill Neidig, the Damon Runyon Cancer Research Foundation (DRG-2017-09), NIH1DP2OD022550-01, 1-R00-GM104148-01, 5U19AI116484-02, and U19 AI104209. M.A. is supported by NIH1-DP5-OD019822. S.C.B. and M.A. are supported by NIH1R01AG056287-01, 1R01AG057915-01, and 1U24CA224309-01, the Bill and Melinda Gates Foundation, and a Translational Research Award from the Stanford Cancer Institute. The Stanford Nano Shared Facility is supported by NSF ECCS-1542152. Author Contributions: L.K. acquired and analyzed the data and wrote the manuscript. M.B., D.M., and R.A. performed experiments. S.J. performed manual segmentation. S.V., A.K., and R.W. provided the samples. S.-R.Y. performed TIL scoring. D.V.V. developed DeepCell. S.C.B. and M.A. supervised the work. Declaration of Interests: M.A. and S.C.B. have patents relating to MIBI technology and are board members, shareholders, and consultants in Ionpath Inc.Attached Files
Accepted Version - nihms-1504863.pdf
Supplemental Material - 1-s2.0-S0092867418311000-mmc1.xlsx
Supplemental Material - 1-s2.0-S0092867418311000-mmc2.xlsx
Supplemental Material - 1-s2.0-S0092867418311000-mmc3.xlsx
Files
Additional details
- PMCID
- PMC6132072
- Eprint ID
- 89413
- Resolver ID
- CaltechAUTHORS:20180906-124040516
- DRG-2292-17
- Damon Runyon Cancer Research Foundation
- ALTF 1128-2016
- European Molecular Biology Organization (EMBO)
- Burroughs Wellcome Fund
- Stanford University
- Crowdflower A.I.
- 5R01CA18390402
- NIH
- Christy and Bill Neidig
- DRG-2017-09
- Damon Runyon Cancer Research Foundation
- 1DP2OD022550-01
- NIH
- 1-R00-GM104148-01
- NIH
- 5U19AI116484-02
- NIH
- U19 AI104209
- NIH
- 1R01AG056287-01
- NIH
- 1R01AG057915-01
- NIH
- 1U24CA224309-01
- NIH
- Bill and Melinda Gates Foundation
- Stanford Cancer Institute
- ECCS-1542152
- NSF
- NIH Postdoctoral Fellowship
- Created
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2018-09-07Created from EPrint's datestamp field
- Updated
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2022-03-04Created from EPrint's last_modified field