A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Apr 16

PMID 30982598

Citations 393

Authors

Johanna Wagner

Maria Anna Rapsomaniki

Stephane Chevrier

Tobias Anzeneder

Claus Langwieder

August Dykgers

Martin Rees

Annette Ramaswamy

Simone Muenst

Savas Deniz Soysal

Andrea Jacobs

Jonas Windhager

Karina Silina

Maries van den Broek

Konstantin Johannes Dedes

Maria Rodriguez Martinez

Walter Paul Weber

Bernd Bodenmiller

Affiliations

Soon will be listed here.

Abstract

Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor cell composition, including phenotypic abnormalities and phenotype dominance. Relationship analyses between tumor and immune cells revealed characteristics of ecosystems related to immunosuppression and poor prognosis. High frequencies of PD-L1 tumor-associated macrophages and exhausted T cells were found in high-grade ER and ER tumors. This large-scale, single-cell atlas deepens our understanding of breast tumor ecosystems and suggests that ecosystem-based patient classification will facilitate identification of individuals for precision medicine approaches targeting the tumor and its immunoenvironment.

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References

Chamberlin T, DAmato J, Arendt L . Obesity reversibly depletes the basal cell population and enhances mammary epithelial cell estrogen receptor alpha expression and progenitor activity. Breast Cancer Res. 2017; 19(1):128. PMC: 5707907. DOI: 10.1186/s13058-017-0921-7. View

Hsu J, Hung M . The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016; 35(4):575-588. PMC: 5215954. DOI: 10.1007/s10555-016-9649-6. View

Weber L, Robinson M . Comparison of clustering methods for high-dimensional single-cell flow and mass cytometry data. Cytometry A. 2016; 89(12):1084-1096. DOI: 10.1002/cyto.a.23030. View

Reinert T, Barrios C . Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015; 7(6):304-20. PMC: 4622303. DOI: 10.1177/1758834015608993. View

Dieci M, Griguolo G, Miglietta F, Guarneri V . The immune system and hormone-receptor positive breast cancer: Is it really a dead end?. Cancer Treat Rev. 2016; 46:9-19. DOI: 10.1016/j.ctrv.2016.03.011. View

Neve R, Chin K, Fridlyand J, Yeh J, Baehner F, Fevr T . A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006; 10(6):515-27. PMC: 2730521. DOI: 10.1016/j.ccr.2006.10.008. View

Murphy C, Dickler M . Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies. Endocr Relat Cancer. 2016; 23(8):R337-52. DOI: 10.1530/ERC-16-0121. View

Buisseret L, Garaud S, De Wind A, Van den Eynden G, Boisson A, Solinas C . Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer. Oncoimmunology. 2017; 6(1):e1257452. PMC: 5283629. DOI: 10.1080/2162402X.2016.1257452. View

Sade-Feldman M, Yizhak K, Bjorgaard S, Ray J, de Boer C, Jenkins R . Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018; 175(4):998-1013.e20. PMC: 6641984. DOI: 10.1016/j.cell.2018.10.038. View

10.

McAllister S, Weinberg R . Tumor-host interactions: a far-reaching relationship. J Clin Oncol. 2010; 28(26):4022-8. DOI: 10.1200/JCO.2010.28.4257. View

11.

Coates A, Winer E, Goldhirsch A, Gelber R, Gnant M, Piccart-Gebhart M . Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015; 26(8):1533-46. PMC: 4511219. DOI: 10.1093/annonc/mdv221. View

12.

Rakha E, Starczynski J, Lee A, Ellis I . The updated ASCO/CAP guideline recommendations for HER2 testing in the management of invasive breast cancer: a critical review of their implications for routine practice. Histopathology. 2014; 64(5):609-15. DOI: 10.1111/his.12357. View

13.

Azizi E, Carr A, Plitas G, Cornish A, Konopacki C, Prabhakaran S . Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell. 2018; 174(5):1293-1308.e36. PMC: 6348010. DOI: 10.1016/j.cell.2018.05.060. View

14.

Quail D, Joyce J . Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19(11):1423-37. PMC: 3954707. DOI: 10.1038/nm.3394. View

15.

Rapsomaniki M, Lun X, Woerner S, Laumanns M, Bodenmiller B, Rodriguez Martinez M . CellCycleTRACER accounts for cell cycle and volume in mass cytometry data. Nat Commun. 2018; 9(1):632. PMC: 5809393. DOI: 10.1038/s41467-018-03005-5. View

16.

Bandura D, Baranov V, Ornatsky O, Antonov A, Kinach R, Lou X . Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem. 2009; 81(16):6813-22. DOI: 10.1021/ac901049w. View

17.

Cassetta L, Pollard J . Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018; 17(12):887-904. DOI: 10.1038/nrd.2018.169. View

18.

Giesen C, Wang H, Schapiro D, Zivanovic N, Jacobs A, Hattendorf B . Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods. 2014; 11(4):417-22. DOI: 10.1038/nmeth.2869. View

19.

Fortier A, Van Themsche C, Asselin E, Cadrin M . Akt isoforms regulate intermediate filament protein levels in epithelial carcinoma cells. FEBS Lett. 2010; 584(5):984-8. DOI: 10.1016/j.febslet.2010.01.045. View

20.

Li H, van der Leun A, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi A . Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell. 2019; 176(4):775-789.e18. PMC: 7253294. DOI: 10.1016/j.cell.2018.11.043. View