PO.TB07.01 · 肿瘤生物学
造血干细胞（HSC）浸润与细胞增殖呈负相关，与更好的患者生存相关，而新辅助化疗导致的HSC减少与乳腺癌的不良生存相关
Infiltration of hematopoietic stem cells (HSC) is associated inversely with cell proliferation, with better patient survival, and its reduction by neoadjuvant chemotherapy relates with poor survival in breast cancer
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摘要 Abstract
中文摘要
背景：造血干细胞（HSC），也称血液干细胞，是可自我更新的细胞，能够发育为所有类型的血细胞。它们存在于骨髓和外周血中。然而，HSC在乳腺癌（BC）肿瘤微环境（TME）中的临床意义仍不明确。本研究旨在阐明HSC浸润在BC的TME中的临床意义。
方法：对5,176例BC患者进行了计算机分析，包括大型独立队列——瑞典癌症基因组分析网络-乳腺（SCAN-B）和乳腺癌国际联盟分子分类学（METABRIC），以及多个单细胞测序队列。通过xCell算法鉴定HSC，将HSC水平高的患者定义为在各队列中HSC表达高于中位数者。
结果：通过单细胞转录组分析，HSC占BC TME中所有细胞的比例范围为0.04-0.50%。HSC浸润与其谱系细胞（共同髓系祖细胞和共同淋巴系祖细胞）不相关，但与树突状细胞和基质相关细胞的高浸润相关，与髓系相关细胞（M1巨噬细胞和嗜酸性粒细胞）及淋巴系相关细胞（Th1细胞、Tregs、NK T细胞和记忆B细胞）的低浸润相关。HSC高的BC富集TGF-beta信号、肌生成、凝血和血管生成基因集。另一方面，Hallmark集合中所有细胞增殖相关基因集（E2F靶点、G2M检查点、MYC靶点-v2和有丝分裂纺锤体）富集于HSC低的BC，且HSC浸润在高组织学分级BC和Ki67高表达BC中显著较低。在两个队列的ER+/HER2-中，HSC高的患者与总体生存更好显著相关（均p<0.02），但在TNBC中则不然。有趣的是，当使用新辅助化疗（NAC）时，ER+/HER2-中HSC浸润无生存差异。结合我们发现的NAC显著减少TME中的HSC，我们不得不推测NAC导致的HSC丢失可能促成了其在患者预后中获益的丧失。最后，HSC水平高与肺转移风险显著降低和更好的生存相关，但与脑转移和骨转移无关。
结论：这是首份采用转录组量化TME中HSC的报告，证明它们罕见，与细胞增殖呈负相关，并与ER+/HER2- BC患者更好的生存相关。HSC浸润的生存获益因减少其浸润的NAC而丧失。HSC高的BC与较低的肺转移风险和更好的生存相关，但与脑转移或骨转移无关。
查看英文原文 English abstract
Background: Hematopoietic stem cell (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 breast cancer (BC) tumor microenvironment (TME) remains unknown. The aim of this study was to elucidate the clinical significance of HSC infiltration in the TME of 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-beta 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 loss of 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 in TME using transcriptome 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.
利益披露 Disclosure
M. Oshi, None.