Triple-Negative Breast Cancer Shapes the Systemic Immune Landscape and Alters Neutrophil Functionality [bulkRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1101001 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28712662.fastq.gz | Fastqsanger.gz | |||
| SRR28712663.fastq.gz | Fastqsanger.gz | |||
| SRR28712664.fastq.gz | Fastqsanger.gz | |||
| SRR28712665.fastq.gz | Fastqsanger.gz | |||
| SRR28712666.fastq.gz | Fastqsanger.gz |
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Project description:Little is known about how commensal colonization controls neutrophil differentiation and functions. Using system immunology approaches we discovered commensal and infection induced changes in neutrophil proteomes. The identified differentially expressed genes were CRISPRed out in immortalized neutrophil progenitor cell lines transduced with lenti-guides. Analysis of maturation and bactericidal capacity of the generated CRISPRed clones ascribed a function to a currently unknown protein-termed Prenylcysteine oxidase 1 like (Pcyox1l). Pcyox1l deficient neutrophils show dramatic defects in longevity, autophagy, and bactericidal functions associated with reductions in SerpinB1a transcripts and protein. Metabolic labeling experiments revealed that Pcyox1l controls levels of protein prenylation, highlighting its key enzymatic function. The Pcyox1l deficiency phenotype is phenocopied by SerpinB1a deficiency in neutrophils signifying linked mechanisms. Commensal colonization increases Pcyox1l and SerpinB1a levels in polymorphonuclear leukocytes (PMNs) in specific pathogen free (SPF) mice when compared to germ free (GF) mice and, conversely, Pcyox1l KO mice demonstrated altered commensal microbiome and elevated susceptibility to bacterial infection. Cumulatively, our data highlight a novel metabolic pathway which is controlled by commensal colonization and governs neutrophil functionality, longevity, and bactericidal properties. In lieu with the impairment of neutrophil bactericidal functions, Pcyox1l KO mice showed elevated susceptibility to infection with the Gram-negative pathogen Pseudomonas aeruginosa
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Project description:Cancer disrupts intratumoral innate-adaptive immune crosstalk, but how the systemic immune landscape evolves during breast cancer progression remains unclear. We profiled circulating immune cells in stage I-III and stage IV triple-negative breast cancer (TNBC) patients and healthy donors (HDs). Metastatic TNBC (mTNBC) patients had reduced T cells, dendritic cells, and differentiated B cells compared to non-metastatic TNBC patients and HDs, partly linked to prior chemotherapy. Vδ1 γδ T cells from mTNBC patients produced more IL17 than those from HDs. Chemotherapy-naïve mTNBC patients showed increased classical monocytes and neutrophils. Transcriptional, proteomic, and functional analyses revealed that neutrophils in mTNBC exhibited enhanced migratory capacity, elevated granule proteins, and higher ROS production. Some immune changes, such as reduced non-switched B cells and heightened neutrophil migration, were evident in earlier TNBC stages. This study comprehensively maps systemic immunity in TNBC, guiding future research on patient stratification and immunomodulation strategies.
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