GSE137300
Immune effector monocyte - neutrophil cooperation induced by the primary tumor prevents metastatic progression of breast cancer
Metastatic behaviour varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking but could underlie the development of novel immunotherapeutic target molecules. Here we show interplay between non-metastatic primary breast cancer and innate immune response, acting together to control metastatic progression. The primary tumor systemically recruits IFN?-producing immune effector monocytes to the lung. IFN? upregulates Tmem173/STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal Tmem173/STINGhigh neutrophils target disseminated tumor cells in the lungs, preventing metastatic outgrowth. Importantly, our findings could underlie the development of immunotherapeutic target molecules that augment the function of immune effector monocytes and Tmem173high neutrophils. Overall design: The aim is to compare the transcriptome of neutrophils and monocytes CCR2+ purified from lungs of NOD/scid mice bearing the highly metastatic tumors HCl-001 (TN1) and low metastatic tumors HCl-002 (TN2). RNA sequencing was performed on RNA extracted from FACS-sorted monocytes CCR2+ and neutrophils from lungs of mice bearing tumors HCl-001 and HCl-002 reaching end point, followed by purification using an RNeasy Micro Kit (Qiagen). cDNA synthesis and whole, transcriptome amplification was performed using the Smart-seq2 protocol, libraries were prepared using Illumina XT Library Preparation Kit and sequenced by HiSeq 2500 sequencer. Raw reads were aligned to reference transcriptome (Mus_musculus.GRCm38) and transcripts per million values were calculated using Kallisto50 quant, version 0.42.3 (2). AltAnalyze was used to analyze normalized read counts and to calculate differentially expressed genes.