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Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in TNBC but still encounters low overall response. Neutrophils, the most abundant leukocytes in the body, are increasingly recognized as an active cancer-modulating entity. In the bloodstream, neutrophils escort circulating tumor cells to promote their survival and stimulate their proliferation and metastasis. In the tumor microenvironment, neutrophils modulate the immune milieu through polarization between the anti-tumor and the pro-tumor phenotypes. Through a comprehensive review of recently published literature, it is evident that neutrophils are an important player in TNBC immunobiology and can be used as an important prognostic marker of TNBC. Particularly, in their pro-tumor form, neutrophils facilitate TNBC metastasis through formation of neutrophil extracellular traps and the pre-metastatic niche. These findings will help advance the potential utilization of neutrophils as a therapeutic target in TNBC.

SUBMITTER: Zheng C

PROVIDER: S-EPMC10373263 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.

Zheng Chanjuan C Xu Xi X Wu Muyao M Xue Lian L Zhu Jianyu J Xia Hongzhuo H Ding Siyu S Fu Shujun S Wang Xinyu X Wang Yian Y He Guangchun G Liu Xia X Deng Xiyun X

Breast cancer research : BCR 20230726 1

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in TNBC but still encounters low overall response. Neutrophils, the most abundant leukocytes in the body, are increasingly recognized as an active cancer-modulating entity. In the bloodstream, neutrophils escort circulating tumor cells to promote their survival and stimulate their proliferati ...[more]

PMID: 37496019

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Project description:Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO (CXCL1/2/3) chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.

Project description:IntroductionTriple-negative breast cancers need to be refined in order to identify therapeutic subgroups of patients.MethodsWe conducted an unsupervised analysis of microarray gene-expression profiles of 107 triple-negative breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. A triple-negative external cohort (n=87) was used for validation.ResultsFuzzy clustering separated triple-negative tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean=64.6 years) than C2 (mean=56.8 years; P=0.03) and C3 patients (mean=51.9 years; P=0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P<0.0001 for both comparisons). Significant event-free survival (P=0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P=0.01) and C2 (P=0.02). Event-free survival analysis results were confirmed when our cohort was pooled with the external cohort (n=194; P=0.01). Functional annotation showed that 22% of triple-negative patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response and low M2-like macrophages were a hallmark of C3, and that these patients had a better event-free survival than C2 patients, characterized by low immune response and high M2-like macrophages: P=0.02 for our cohort, and P=0.03 for pooled cohorts.ConclusionsWe identified three subtypes of triple-negative patients: luminal androgen receptor (22%), basal-like with low immune response and high M2-like macrophages (45%), and basal-enriched with high immune response and low M2-like macrophages (33%). We noted out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in triple-negative basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype triple-negative patients.

Project description:Triple-negative (TN) breast cancers need to be refined in order to identify therapeutic subgroups of patients. We conducted an unsupervised analysis of microarray gene-expression profiles of 107 TN breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. An 87 TN external cohort was used for validation. Fuzzy clustering separated TN tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean = 64.6 years) than C2 (mean = 56.8 years; P = 0.03) and C3 patients (mean = 51.9 years; P = 0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P < 0.0001 for both comparisons). Significant event-free survival (EFS) (P = 0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P = 0.01) and C2 (P = 0.02). EFS analysis results were confirmed when our cohort was pooled with external cohort (n = 194; P = 0.01). Functional annotation showed that 22% of TN patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor [LAR]). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes, but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response (HIR) and low M2-like macrophages were a hallmark of C3, and that these patients had a better EFS than C2 patients, characterized by low immune response (LIR) and high M2-like macrophages: P = 0.02 for our cohort, and P = 0.03 for pooled cohorts. We identified 3 subtypes of TN patients: LAR (22%), basal-like with LIR and high M2-like macrophages (45%) and basal-enriched with HIR and low M2-like macrophages (33%). We pointed out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in TN basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype TN patients. Subtyping molecular characterization within a cohort of 107 TN-IHC by means of gene expression profiling

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Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.

Publications

Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.

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