TY - JOUR
T1 - A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging
AU - Keren, Leeat
AU - Bosse, Marc
AU - Marquez, Diana
AU - Angoshtari, Roshan
AU - Jain, Samir
AU - Varma, Sushama
AU - Yang, Soo-Ryum
AU - Kurian, Allison
AU - Van Valen, David
AU - West, Robert
AU - Bendall, Sean C.
AU - Angelo, Michael
N1 - 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 NIH 5R01CA18390402. S.C.B. is supported by a gift from Christy and Bill Neidig, the Damon Runyon Cancer Research Foundation (DRG-2017-09), NIH 1DP2OD022550-01, 1-R00-GM104148-01, 5U19AI116484-02, and U19 AI104209. M.A. is supported by NIH 1-DP5-OD019822. S.C.B. and M.A. are supported by NIH 1R01AG056287-01, 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.
PY - 2018/9/6
Y1 - 2018/9/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052874515&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.08.039
DO - 10.1016/j.cell.2018.08.039
M3 - مقالة
SN - 0092-8674
VL - 174
SP - 1373
EP - 1387
JO - Cell
JF - Cell
IS - 6
ER -