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

Ik Sun Kim, Yang Gao, Thomas Welte, Hai Wang, Jun Liu, Mahnaz Janghorban, Kuanwei Sheng, Yichi Niu, Amit Goldstein, Na Zhao, Igor Bado, Hin Ching Lo, Michael J. Toneff, Tuan Nguyen, Wen Bu, Weiyu Jiang, James Arnold, Franklin Gu, Jian He, Deborah JebakumarKimberly Walker, Yi Li, Qianxing Mo, Thomas F. Westbrook, Chenghang Zong, Arundhati Rao, Arun Sreekumar, Jeffrey M. Rosen, Xiang H.F. Zhang

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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.

Original languageEnglish
Pages (from-to)1113-1126
Number of pages14
JournalNature Cell Biology
Volume21
Issue number9
DOIs
StatePublished - 1 Sep 2019
Externally publishedYes

Fingerprint

Dive into the research topics of 'Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms'. Together they form a unique fingerprint.

Cite this