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Nat Cell Biol. 2019 Sep;21(9):1113-1126. doi: 10.1038/s41556-019-0373-7. Epub 2019 Aug 26.

Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms.

Kim IS1,2,3,4, Gao Y3,4, Welte T1,3,4, Wang H1,3,4, Liu J1,3,4, Janghorban M3,4, Sheng K2,3,5, Niu Y3,5, Goldstein A1,3,4, Zhao N3,4, Bado I1,3,4, Lo HC1,2,3,4, Toneff MJ3,4,6, Nguyen T3,4,7, Bu W1,3,4, Jiang W1,3,4, Arnold J3,8, Gu F3,8, He J9, Jebakumar D9, Walker K6, Li Y1,3,4, Mo Q5,10, Westbrook TF3,5,8, Zong C3,5,11, Rao A9, Sreekumar A3,4, Rosen JM3,4, Zhang XH12,13,14,15.

Author information

1
Lester and Sue Smith Breast Center, Houston, TX, USA.
2
Integrative Molecular and Biomedical Sciences Graduate Program, Houston, TX, USA.
3
Dan L. Duncan Cancer Center, Houston, TX, USA.
4
Department of Molecular and Cellular Biology, Houston, TX, USA.
5
Department of Molecular and Human Genetics, Houston, TX, USA.
6
Department of Biology, Widener University, One University Place, Chester, PA, USA.
7
Graduate Program in Translational Biology and Molecular Medicine, Houston, TX, USA.
8
Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Houston, TX, USA.
9
Scott and White Medical Center, Baylor Scott and White Healthcare, Temple, Texas, USA.
10
Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
11
McNair Medical Institute Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
12
Lester and Sue Smith Breast Center, Houston, TX, USA. xiangz@bcm.edu.
13
Dan L. Duncan Cancer Center, Houston, TX, USA. xiangz@bcm.edu.
14
Department of Molecular and Cellular Biology, Houston, TX, USA. xiangz@bcm.edu.
15
McNair Medical Institute Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA. xiangz@bcm.edu.

Abstract

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.

PMID:
31451770
PMCID:
PMC6726554
[Available on 2020-02-26]
DOI:
10.1038/s41556-019-0373-7

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