Association of infiltration of hematopoietic stem cells (HSC) with cell proliferation and patient survival in breast cancer.

Abstract

562 Background: HSCs, also known as blood stem cells, are self-renewable cells that can develop into all types of blood cells. They are found in bone marrow and peripheral blood. However, the clinical relevance of HSCs in the BC TME remains unknown.To elucidate the clinical significance of HSC infiltration in the tumor microenvironment (TME) of breast cancer (BC). Methods: In silico analyses were conducted on 5,176 BC patients, including large independent cohorts; The Sweden Cancerome Analysis Network-Breast (SCAN-B) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), as well as multiple single-cell sequenced cohorts. HSC were identified through the xCell algorithm, and patients with high HSC levels were defined as those with HSC expression above the median in each cohort. Results: Fraction of HSCs ranged from 0.04-0.50% of all cells in BC TME by single cell transcriptome analyses. HSC infiltration was not correlated with its lineage cells, common myeloid progenitor cells and common lymphoid progenitor cells, but was associated with high infiltration of dendritic cells and stromal-related cells and low infiltration of Myeloid-related cells; M1-macrophages, and eosinophils, and lymphoid-related cells; Th1 cells, Tregs, NK T cells, and memory B cells. HSC high BC enriched TGF-β signaling, myogenesis, coagulation, and angiogenesis gene sets. On the other hand, all the cell proliferation-related gene sets in Hallmark collection; E2F targets, G2M checkpoint, MYC targets-v2, and mitotic spindle, enriched to low HSC BC, and HSC infiltration was significantly lower in high histological grade BC and in Ki67 high expression BC. HSC high patients were significantly associated with better overall survival compared to low patients in ER+/HER2- (both p<0.02), but not in TNBC in both cohorts. Interestingly, there was no survival difference by HSC infiltration in ER+/HER2- when neoadjuvant chemotherapy (NAC) was used. Together with our finding that HSC in the TME markedly reduced by NAC, we cannot help but speculate that the loss of HSCs by NAC may have contributed to lose their benefit in patient prognosis. Lastly, high levels of HSC were associated with significantly lower risk of lung metastasis and better survival, but not with brain and bone metastases. Conclusions: This is the first report that quantified HSCs using transcriptome in TME and demonstrated that they are rare, associated inversely with cell proliferation and with better survival in ER+/HER2- BC patients. Survival benefit of HSC infiltration was lost with NAC that reduce its infiltration. HSC high BC was associated with lower risk of lung metastasis and with better survival, but not with brain nor bone metastasis.