Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms.
Ik Sun KimYang GaoThomas WelteHai WangJun LiuMahnaz JanghorbanKuanwei ShengYichi NiuAmit GoldsteinNa ZhaoIgor BadoHin-Ching LoMichael J ToneffTuan NguyenWen BuWeiyu JiangJames ArnoldFranklin GuJian HeDeborah JebakumarKimberly WalkerYi LiQianxing MoThomas F WestbrookChenghang ZongArundhati RaoArun SreekumarJeffrey M RosenXiang H F ZhangPublished in: Nature cell biology (2019)
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.
Keyphrases
- dendritic cells
- immune response
- single cell
- bone marrow
- acute myeloid leukemia
- regulatory t cells
- rna seq
- cell therapy
- case report
- stem cells
- cell cycle arrest
- papillary thyroid
- toll like receptor
- adipose tissue
- peripheral blood
- high glucose
- cell proliferation
- cell death
- drug induced
- squamous cell carcinoma
- african american
- squamous cell
- human health
- risk assessment