AbstractBreast cancer categorized into hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative (TNBC) subtypes, exhibits varied outcomes based on the number of tumor-infiltrating lymphocytes (TILs). To explore the divergent roles of TIL levels across different subtypes, we employed single-cell RNA sequencing on 31 patients with breast cancer.

摘要乳腺癌分为激素受体阳性（HR+），HER2阳性（HER2+）和三阴性（TNBC）亚型，根据肿瘤浸润淋巴细胞（TIL）的数量表现出不同的结果。为了探索TIL水平在不同亚型中的不同作用，我们对31例乳腺癌患者进行了单细胞RNA测序。

HR+ breast cancer with high TIL levels (TIL-high) revealed increased SPP1+ macrophages, increased SPP1 expression in other monocytes/macrophages (mono/macro) subgroups, and enriched pathways associated with extracellular matrix (ECM) remodeling in mono/macro. Moreover, cell–cell interaction analyses revealed enhanced SPP1, MIF, and FN1 signaling in the interaction between SPP1+ macrophages and T-cells in TIL-high HR+ breast cancer.

具有高TIL水平（TIL高）的HR+乳腺癌显示SPP1+巨噬细胞增加，其他单核细胞/巨噬细胞（单核/巨噬细胞）亚组中SPP1表达增加，以及单核/巨噬细胞中与细胞外基质（ECM）重塑相关的富集途径。此外，细胞间相互作用分析显示，在TIL高HR+乳腺癌中，SPP1+巨噬细胞与T细胞之间的相互作用中，SPP1，MIF和FN1信号增强。

Spatial transcriptomics data highlighted the close proximity of SPP1+ macrophages, CD8+ T-cells, and CD4+ T-cells in TIL-high HR+ breast cancer. Our findings unveil the novel influence of SPP1+ macrophages on T-cells in TIL-high HR+ breast cancer, potentially explaining the poor prognosis and offering insights for targeted interventions..

空间转录组学数据强调了TIL高HR+乳腺癌中SPP1+巨噬细胞，CD8+T细胞和CD4+T细胞的紧密接近。我们的研究结果揭示了SPP1+巨噬细胞对TIL高HR+乳腺癌中T细胞的新影响，可能解释了预后不良，并为靶向干预提供了见解。。

IntroductionBreast cancer is the second most prevalent type of cancer globally, with an age-standardized incidence rate of 46.8 per 100,000 people in 20221. It can be classified into three subtypes based on the expression of hormone and HER2 receptors: hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative breast cancer (TNBC)2.

引言乳腺癌是全球第二大最常见的癌症类型，20221年的年龄标准化发病率为每10万人46.8。根据激素和HER2受体的表达，它可以分为三种亚型：激素受体阳性（HR+），HER2阳性（HER2+）和三阴性乳腺癌（TNBC）2。

A critical prognostic factor in breast cancer is the level of tumor-infiltrating lymphocytes (TILs), which can be assessed through histologic examination3. TILs are defined as mononuclear cells, (including plasma cells) that infiltrate the stromal tissue within the invasive tumor area4. TILs exhibit subtype-specific characteristics, wherein HER2+ breast cancer and TNBC typically manifest higher TIL levels than those of HR+ breast cancer5.

。TILs被定义为浸润侵袭性肿瘤区域内基质组织的单核细胞（包括浆细胞）4。TIL表现出亚型特异性特征，其中HER2+乳腺癌和TNBC通常表现出比HR+乳腺癌更高的TIL水平5。

In HER2+ breast cancer and TNBC, increased TIL levels are associated with improved pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC), longer disease-free survival, and overall survival6. Conversely, in HR+ breast cancer, higher TIL levels are linked to shorter overall survival7,8.Numerous immune cell types can modulate TIL function within the tumor microenvironment (TME)9.

在HER2+乳腺癌和TNBC中，TIL水平升高与新辅助化疗（NAC）后病理完全缓解（pCR）率提高，无病生存期延长和总体生存率相关6。相反，在HR+乳腺癌中，较高的TIL水平与较短的总体存活率相关[7,8]。许多免疫细胞类型可以调节肿瘤微环境（TME）9内的TIL功能。

Among these, tumor-associated macrophages (TAMs) represent a significant proportion of breast cancer immune cells and are closely related to unfavorable prognoses10,11. Single-cell RNA sequencing (scRNA-seq) studies have revealed specific TAM subsets linked to T-cell infiltration and immunosuppression in patients with breast cancer12,13.One of the specific TAM subsets, SPP1+ macrophages, plays a crucial role in the TME of various cancers.

其中，肿瘤相关巨噬细胞（TAMs）占乳腺癌免疫细胞的很大比例，与不良预后密切相关10,11。单细胞RNA测序（scRNA-seq）研究揭示了与乳腺癌患者T细胞浸润和免疫抑制相关的特定TAM亚群12,13。特定TAM亚群之一SPP1+巨噬细胞在各种癌症的TME中起着至关重要的作用。

For example, in Colorectal cancer (CRC), the presence of SPP1+ macrophages is closely correlated with tumor-specific FAP+ fibroblasts, resulting in a desmop.

例如，在结直肠癌（CRC）中，SPP1+巨噬细胞的存在与肿瘤特异性FAP+成纤维细胞密切相关，导致结蛋白。

SPP1+ macrophages and mono/macro in TIL-high group enriched in ECM remodeling-associated pathways in HR+ breast cancerTo explore the characteristics of SPP1+ macrophages in HR+ breast cancer, we performed pathway enrichment analysis with DEGs of SPP1+ macrophages with other mono/macro. From the analysis of DEGs, we identified 24 genes with up-regulated expression with an average log2 fold change greater than 1 and a p-value less than 0.05, including MMP12, SPP1, and NURP1.

在HR+乳腺癌中富含ECM重塑相关途径的TIL高组中的SPP1+巨噬细胞和单/宏为了探索HR+乳腺癌中SPP1+巨噬细胞的特征，我们用SPP1+巨噬细胞的DEG与其他单/宏进行了途径富集分析。从DEGs的分析中，我们鉴定出24个表达上调的基因，平均log2倍变化大于1，p值小于0.05，包括MMP12，SPP1和NURP1。

These genes were subsequently selected for pathway enrichment analysis (Fig. 3a). In this analysis, pathways related to ECM remodeling, such as ECM degradation, collagen degradation, and ECM organization, were significantly enriched in SPP1+ macrophages from HR+ breast cancer (Fig. 3b). In other subgroups of mono/macro, the CTSK+ macrophages subgroup tended to increase in the TIL-high group without statistical significance, enriched in similar pathways related to ECM remodeling (Supplementary Fig.

随后选择这些基因进行途径富集分析（图3a）。在该分析中，与ECM重塑相关的途径，例如ECM降解，胶原降解和ECM组织，在来自HR+乳腺癌的SPP1+巨噬细胞中显着富集（图3b）。在单/宏的其他亚组中，CTSK+巨噬细胞亚组倾向于在TIL高组中增加而无统计学意义，富含与ECM重塑相关的类似途径（Supplementary Fig.）。

4a).Fig. 3: Pathways related to ECM remodeling process and SPP1 are increased in TIL-high HR+ breast cancer mono/macro.a Volcano plot of DEGs between SPP1+ macro and other mono/macro subgroups of HR+ breast cancer. Red dots indicate DEGs. b Bar plot shows enriched pathways of genes upregulated in SPP1+ macro.

4a）。图3:TIL高HR+乳腺癌单/宏中与ECM重塑过程和SPP1相关的途径增加。SPP1+宏和HR+乳腺癌的其他单/宏亚组之间的DEG火山图。红点表示DEG。b条形图显示在SPP1+宏中上调的基因的富集途径。

c Volcano plot of DEGs between HR+ mono/macro of TIL-high and TIL-low group. Red dots indicate DEGs. d Bar plot shows enriched pathways of genes upregulated in TIL-high HR+ mono/macro. e Feature plot shows level of SPP1 expression in HR+ Mono/macro in accordance with the TIL levels. f Violin plot shows level of SPP1 expression in HR+ Mono/macro in accordance with the TIL levels.

c TIL高和TIL低组的HR+单/宏之间的DEG火山图。红点表示DEG。d条形图显示在TIL高HR+单/宏中上调的基因的富集途径。e特征图显示了根据TIL水平在HR+单/宏中SPP1表达的水平。f小提琴图显示根据TIL水平，HR+单/宏中SPP1表达水平。

SPP1+ macro SPP1+ macrophages, DEGs differentially expressed genes, macro macrophages, mono/macro monocytes, and macrophages, .

SPP1+大SPP1+巨噬细胞，DEGs差异表达基因，大巨噬细胞，单/大单核细胞和巨噬细胞。

SPP1+ macrophages in TIL-high HR+ breast cancer interact more with T-cells via SPP1, MIF, and FN1 signalingCell–cell interaction analyses were performed to study the interactions of SPP1+ macrophages with other immune cells using CellChat22. We initially compared TIL-high and low HR+ breast cancer with differential number of interactions and interaction strength (Fig.

TIL高HR+乳腺癌中的SPP1+巨噬细胞通过SPP1，MIF和FN1信号与T细胞相互作用更多。使用CellChat22进行细胞间相互作用分析，以研究SPP1+巨噬细胞与其他免疫细胞的相互作用。我们最初比较了TIL高和低HR+乳腺癌与不同数量的相互作用和相互作用强度（图）。

4a, b). The TIL-high group displayed a higher number of interactions within mono/macro, CD4T, and CD8T, as well as enriched interaction numbers among mono/macro, CD4T, and CD8T (Fig. 4a). Notably, the interaction strength, especially from mono/macro to CD8T and CD4T, exhibited greater intensity in the TIL-high group (Fig.

4a，b）。TIL高组在单/宏，CD4T和CD8T中显示出更多的相互作用，以及单/宏，CD4T和CD8T之间丰富的相互作用数（图4a）。值得注意的是，相互作用强度，特别是从单/宏观到CD8T和CD4T，在TIL高组中表现出更大的强度（图）。

4b). Consequently, we proceeded to analyze which signaling interactions were involved in the direction from mono/macro to CD8T and CD4T. When analyzed for each cell subgroup, the interaction number and strength were most pronounced in TIL-high when CD8 naive and CD8 proliferating were the target cells (Supplementary Fig.

4b）。因此，我们继续分析从单/宏到CD8T和CD4T的方向涉及哪些信号相互作用。当分析每个细胞亚组时，当CD8幼稚和CD8增殖是靶细胞时，TIL高的相互作用数和强度最为明显（Supplementary Fig.）。

7a). Comprehensive analysis of mono/macro towards CD8T and CD4T within the HR+ subtype identified significant enrichment of 19 signaling pathways in the TIL-high group (Fig. 4c). When analyzing the interaction in the directions of CD8T and CD4T separately, the signaling pathways enriched in TIL-high did not differ substantially from the previous results (19 per 19 pathways matched in CD8T, and 12 per 19 pathways matched in CD4T) (Supplementary Fig.

7a）。对HR+亚型内CD8T和CD4T的单/宏的综合分析确定了TIL高组中19个信号传导途径的显着富集（图4c）。当分别分析CD8T和CD4T方向上的相互作用时，富含TIL-high的信号传导途径与先前的结果没有显着差异（CD8T中匹配的19个途径中有19个，CD4T中匹配的19个途径中有12个）（补充图。

7b). Therefore, we conducted a combined analysis of interactions from mono/macro to both cell groups. Among the 19 signaling pathways examined, 7 pathways (RESISTIN, SN, VCAM, PARs, IL10, IL16, and PECAM1) showed enrichment exclusively in the TIL-high group, while 12 pathways (CD99, SPP1, CD86, CLEC, MIF, FN1, NECTIN, CCL, APP,.

7b）。因此，我们对从单/宏到两个细胞组的相互作用进行了综合分析。在检测的19条信号通路中，7条通路（抵抗素、SN、VCAM、PARs、IL10、IL16和PECAM1）仅在TIL高组中富集，而12条通路（CD99、SPP1、CD86、CLEC、MIF、FN1、NECTIN、CCL、APP、），。

Data availability

数据可用性

The datasets in this study are available from the Gene Expression Omnibus (GSE261774). The public data used in the research have been specified in the main manuscript.

本研究中的数据集可从Gene Expression Omnibus（GSE261774）获得。研究中使用的公共数据已在主要手稿中指定。

ReferencesFerlay, J. et al. Global Cancer Observatory: Cancer Today https://gco.iarc.fr/today (2020).Loibl, S., Poortmans, P., Morrow, M., Denkert, C. & Curigliano, G. Breast cancer. Lancet 397, 1750–1769 (2021).Article

参考文献Ferlay，J。等人，《全球癌症观察站：今日癌症》https://gco.iarc.fr/today（2020年）。Loibl，S.，Poortmans，P.，Morrow，M.，Denkert，C。和Curigliano，G。乳腺癌。柳叶刀3971750-1769（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Loi, S. et al. The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition. Ann. Oncol. 32, 1236–1244 (2021).Article

Loi，S.等人，《肿瘤浸润淋巴细胞作为乳腺癌生物标志物的历程：检查点抑制时代的临床应用》。安科。32236-1244（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Salgado, R. et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259–271 (2015).Article

Salgado，R.等人，《乳腺癌中肿瘤浸润淋巴细胞（TILs）的评估：2014年国际TILs工作组的建议》。安科。26259-271（2015）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Stanton, S. E., Adams, S. & Disis, M. L. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol. 2, 1354–1360 (2016).Article

Stanton，S.E.，Adams，S。＆Disis，M.L。乳腺癌亚型中肿瘤浸润淋巴细胞发生率和程度的变化：系统评价。JAMA Oncol。21354-1360（2016）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Gao, Z. H., Li, C. X., Liu, M. & Jiang, J. Y. Predictive and prognostic role of tumour-infiltrating lymphocytes in breast cancer patients with different molecular subtypes: a meta-analysis. BMC Cancer 20, 1150 (2020).Article

Gao，Z.H.，Li，C.X.，Liu，M。＆Jiang，J.Y。肿瘤浸润淋巴细胞在不同分子亚型乳腺癌患者中的预测和预后作用：荟萃分析。BMC癌症201150（2020）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Makhlouf, S. et al. Evaluation of tumour infiltrating lymphocytes in luminal breast cancer using artificial intelligence. Br. J. Cancer 129, 1747–1758 (2023).Article

Makhlouf，S.等人。使用人工智能评估管腔乳腺癌中的肿瘤浸润淋巴细胞。《癌症杂志》1291747-1758（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Denkert, C. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19, 40–50 (2018).Article

Denkert，C.等人，《不同亚型乳腺癌的肿瘤浸润淋巴细胞与预后：对3771例接受新辅助治疗的患者的汇总分析》。柳叶刀Oncol。。文章

PubMed

PubMed

Google Scholar

谷歌学者

Labani-Motlagh, A., Ashja-Mahdavi, M. & Loskog, A. The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses. Front. Immunol. 11, 940 (2020).Article

Labani-Motlagh，A.，Ashja-Mahdavi，M。＆Loskog，A。肿瘤微环境：阻碍和阻碍抗肿瘤免疫反应的环境。正面。免疫。11940（2020）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Christofides, A. et al. The complex role of tumor-infiltrating macrophages. Nat. Immunol. 23, 1148–1156 (2022).Article

Christofides，A。等人。肿瘤浸润巨噬细胞的复杂作用。自然免疫。231148-1156（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Qiu, S. Q. et al. Tumor-associated macrophages in breast cancer: Innocent bystander or important player? Cancer Treat. Rev. 70, 178–189 (2018).Article

Qiu，S.Q.等。乳腺癌中的肿瘤相关巨噬细胞：无辜的旁观者还是重要的参与者？癌症治疗。。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Timperi, E. et al. Lipid-associated macrophages are induced by cancer-associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res. 82, 3291–3306 (2022).Article

脂质相关巨噬细胞由癌症相关成纤维细胞诱导，并介导乳腺癌的免疫抑制。癌症研究823291-3306（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Nalio Ramos, R. et al. Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer. Cell 185, 1189–1207.e1125 (2022).Article

Nalio Ramos，R。等人。组织驻留的FOLR2（+）巨噬细胞与人乳腺癌中CD8（+）T细胞浸润相关。细胞1851189-1207.e1125（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Qi, J. et al. Single-cell and spatial analysis reveal interaction of FAP(+) fibroblasts and SPP1(+) macrophages in colorectal cancer. Nat. Commun. 13, 1742 (2022).Article

Qi，J。等人。单细胞和空间分析揭示了FAP（+）成纤维细胞和SPP1（+）巨噬细胞在结直肠癌中的相互作用。。131742（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bill, R. et al. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science 381, 515–524 (2023).Article

Bill，R。等人CXCL9:SPP1巨噬细胞极性识别了控制人类癌症的细胞程序网络。科学381515-524（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Goldberg, J. et al. The immunology of hormone receptor positive breast cancer. Front. Immunol. 12, 674192 (2021).Article

Goldberg，J.等人，《激素受体阳性乳腺癌的免疫学》。正面。免疫。12674192（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bense, R. D. et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djw192 (2017).Hu, Q. et al. Atlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling.

Bense，R.D.等人。肿瘤浸润性免疫细胞组成和功能与乳腺癌疾病预后的相关性。J、 国家癌症研究所。https://doi.org/10.1093/jnci/djw192（2017年）。Hu，Q。等人。通过配对单细胞RNA测序和抗原受体谱分析揭示乳腺癌浸润的B淋巴细胞图谱。

Nat. Commun. 12, 2186 (2021).Article .

Nat.普通。122186（2021）。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 e3529 (2021).Article

Hao，Y.等人。多模式单细胞数据的综合分析。细胞1843573–3587 e3529（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Andrew, B., Charlotte, D., Yuhan, H., Paul, H. & Rahul, S. Azimuth: A Shiny App Demonstrating a Query-Reference Mapping Algorithm for Single-Cell Data https://github.com/satijalab/azimuth (2022).Ma, R. Y., Black, A. & Qian, B. Z. Macrophage diversity in cancer revisited in the era of single-cell omics.

Andrew，B.，Charlotte，D.，Yuhan，H.，Paul，H.＆Rahul，S.Azizontation：一个闪亮的应用程序，演示了单细胞数据的查询参考映射算法https://github.com/satijalab/azimuth（2022年）。Ma，R.Y.，Black，A。＆Qian，B.Z。在单细胞组学时代重新审视癌症中的巨噬细胞多样性。

Trends Immunol. 43, 546–563 (2022).Article .

趋势免疫。43546-563（2022）。文章。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).Article

Jin，S.等人。使用CellChat推断和分析细胞间通信。。121088（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wu, S. Z. et al. A single-cell and spatially resolved atlas of human breast cancers. Nat. Genet. 53, 1334–1347 (2021).Article

Wu，S.Z.等人。人类乳腺癌的单细胞和空间分辨图谱。纳特·吉内特。531334-1347（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Brueffer, C. et al. Clinical value of RNA sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: a report from the population-based multicenter sweden cancerome analysis network-breast initiative. JCO Precis. Oncol. https://doi.org/10.1200/po.17.00135 (2018).Abdulla, S.

Brueffer，C.等人。基于RNA测序的分类器预测五种常规乳腺癌生物标志物的临床价值：来自基于人群的多中心瑞典癌症分析网络乳腺倡议的报告。JCO Precis公司。Oncol公司。https://doi.org/10.1200/po.17.00135。阿卜杜拉，S。

et al. CZ CELL×GENE Discover: a single-cell data platform for scalable exploration, analysis and modeling of aggregated data. Preprint at bioRxiv https://doi.org/10.1101/2023.10.30.563174, https://cellxgene.cziscience.com/docs/08__Cite%20cellxgene%20in%20your%20publications (2023).Chakraborty, G., Jain, S.

CZ CELL×GENE Discover：用于聚合数据的可扩展探索，分析和建模的单细胞数据平台。https://doi.org/10.1101/2023.10.30.563174，https://cellxgene.cziscience.com/docs/08__Cite%20cellxgene%20in%20your%20publications。查克拉博蒂，G.，贾恩，S。

& Kundu, G. C. Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res. 68, 152–161 (2008).Article .

&Kundu，G.C。骨桥蛋白通过自分泌和旁分泌机制促进血管内皮生长因子依赖性乳腺肿瘤生长和血管生成。癌症研究68152-161（2008）。文章。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Morse, C. et al. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur. Respir. J. https://doi.org/10.1183/13993003.02441-2018 (2019).Hoeft, K. et al. Platelet-instructed SPP1(+) macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner.

Morse，C。等人。在特发性肺纤维化中增殖表达SPP1/MERTK的巨噬细胞。欧元呼吸。J。https://doi.org/10.1183/13993003.02441-2018（2019年）。Hoeft，K。等人。血小板指导的SPP1（+）巨噬细胞以CXCL4依赖性方式驱动纤维化中的肌成纤维细胞活化。

Cell Rep. 42, 112131 (2023).Article .

细胞代表42112131（2023）。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhang, C. et al. Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling. Oncotarget 7, 45702–45714 (2016).Article

。Oncotarget745702–45714（2016）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sangaletti, S. et al. Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res. 74, 4706–4719 (2014).Article

Sangaletti，S。等人。骨桥蛋白在转移生态位中形成免疫抑制。癌症研究744706-4719（2014）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Yuan, Z. et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol. Cancer 22, 48 (2023).Article

袁，Z。等。肿瘤进展和免疫逃逸中的细胞外基质重塑：从机制到治疗。分子癌症22,48（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Xie, W. et al. Multi-transcriptomic analysis reveals the heterogeneity and tumor-promoting role of SPP1/CD44-mediated intratumoral crosstalk in gastric cancer. Cancers https://doi.org/10.3390/cancers15010164 (2022).He, C. et al. Single-cell transcriptomic analysis revealed a critical role of SPP1/CD44-mediated crosstalk between macrophages and cancer cells in glioma.

Xie，W。等人。多转录组学分析揭示了SPP1/CD44介导的肿瘤内串扰在胃癌中的异质性和肿瘤促进作用。癌症https://doi.org/10.3390/cancers15010164（2022年）。单细胞转录组学分析揭示了SPP1/CD44介导的巨噬细胞和癌细胞之间的串扰在胶质瘤中的关键作用。

Front. Cell Dev. Biol. 9, 779319 (2021).Article .

正面。细胞开发生物学。9779319（2021）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gao, W. et al. SPP1 is a prognostic related biomarker and correlated with tumor-infiltrating immune cells in ovarian cancer. BMC Cancer 22, 1367 (2022).Article

Gao，W。等人。SPP1是一种预后相关的生物标志物，与卵巢癌中的肿瘤浸润性免疫细胞相关。BMC癌症221367（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Salkeni, M. A. & Naing, A. Interleukin-10 in cancer immunotherapy: from bench to bedside. Trends Cancer 9, 716–725 (2023).Article

Salkeni，M.A。＆Naing，A。癌症免疫治疗中的白细胞介素-10：从长凳到床边。趋势癌症9716-725（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Setrerrahmane, S. & Xu, H. Tumor-related interleukins: old validated targets for new anti-cancer drug development. Mol. Cancer 16, 153 (2017).Article

Setrerrahmane，S。＆Xu，H。肿瘤相关白细胞介素：新抗癌药物开发的旧验证靶标。摩尔癌症16153（2017）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Noe, J. T. & Mitchell, R. A. MIF-dependent control of tumor immunity. Front. Immunol. https://doi.org/10.3389/fimmu.2020.609948 (2020).Abe, R., Peng, T., Sailors, J., Bucala, R. & Metz, C. N. Regulation of the CTL response by macrophage migration inhibitory factor. J. Immunol. 166, 747–753 (2001).Article .

Noe，J.T。＆Mitchell，R.A。MIF依赖性肿瘤免疫控制。正面。免疫。https://doi.org/10.3389/fimmu.2020.609948（2020年）。Abe，R.，Peng，T.，Seals，J.，Bucala，R。＆Metz，C.N。巨噬细胞迁移抑制因子对CTL反应的调节。J、 免疫。166747-753（2001）。文章。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Yan, X., Orentas, R. J. & Johnson, B. D. Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation. Cytokine 33, 188–198 (2006).Article

Yan，X.，Orentas，R.J。＆Johnson，B.D。肿瘤衍生的巨噬细胞迁移抑制因子（MIF）抑制T淋巴细胞活化。细胞因子33188-198（2006）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Efthymiou, G. et al. Shaping up the tumor microenvironment with cellular fibronectin. Front. Oncol. https://doi.org/10.3389/fonc.2020.00641 (2020).Wang, H. et al. FN1 is a prognostic biomarker and correlated with immune infiltrates in gastric cancers. Front. Oncol. https://doi.org/10.3389/fonc.2022.918719 (2020).Overstreet, M.

Efthymiou，G。等人。用细胞纤连蛋白塑造肿瘤微环境。正面。Oncol公司。https://doi.org/10.3389/fonc.2020.00641（2020年）。Wang，H。等人。FN1是一种预后生物标志物，与胃癌的免疫浸润有关。正面。Oncol公司。https://doi.org/10.3389/fonc.2022.918719（2020年）。奥弗斯特里特，M。

G. et al. Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin αV. Nat. Immunol. 14, 949–958 (2013).Article .

G、 炎症诱导的效应CD4+T细胞间质迁移依赖于整合素αV。自然免疫。14949-958（2013）。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Trastoy, B., Naegeli, A., Anso, I., Sjogren, J. & Guerin, M. E. Structural basis of mammalian mucin processing by the human gut O-glycopeptidase OgpA from Akkermansia muciniphila. Nat. Commun. 11, 4844 (2020).Article

Trastoy，B.，Naegeli，A.，Anso，I.，Sjogren，J。＆Guerin，M.E。来自Akkermansia muciniphila的人肠道O-糖肽酶OgpA加工哺乳动物粘蛋白的结构基础。。114844（2020）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Criscitiello, C. et al. Tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer. Breast Cancer Res. Treat. 183, 347–354 (2020).Article

Criscitiello，C。等。ER+/HER2乳腺癌中的肿瘤浸润淋巴细胞（TIL）。乳腺癌研究治疗。183347-354（2020）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Gothlin Eremo, A. et al. Evaluation of SPP1/osteopontin expression as predictor of recurrence in tamoxifen treated breast cancer. Sci. Rep. 10, 1451 (2020).Article

Gothlin-Eremo，A。等。SPP1/骨桥蛋白表达作为他莫昔芬治疗乳腺癌复发预测因子的评估。科学。代表101451（2020）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, Z. et al. Drug Gene Budger (DGB): an application for ranking drugs to modulate a specific gene based on transcriptomic signatures. Bioinformatics 35, 1247–1248 (2019).Article

Wang，Z.等人。药物基因预算（DGB）：一种基于转录组特征对药物进行排名以调节特定基因的应用。生物信息学351247-1248（2019）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Poleboyina, P. K. et al. Entrectinib a plausible inhibitor for osteopontin (SPP1) in cervical cancer—integrated bioinformatic approach. Appl. Biochem. Biotechnol. 195, 7766–7795 (2023).Article

Poleboyina，P.K。等人。Entrectinib是宫颈癌综合生物信息学方法中骨桥蛋白（SPP1）的合理抑制剂。应用。生物化学。生物技术。。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).Article

Zheng，G.X.等人。单细胞的大规模并行数字转录谱分析。。814049（2017）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Team, R. C. R.: A Language and Environment for Statistical Computing https://www.R-project.org/ (2021).Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).Article

R.C.R.团队：统计计算的语言和环境https://www.R-project.org/（2021年）。Korsunsky，I。等人。单细胞数据与和谐的快速，灵敏和准确整合。自然方法161289-1296（2019）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yu, G. & He, Q. Y. ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization. Mol. Biosyst. 12, 477–479 (2016).Article

Yu，G。＆He，Q。Y。ReactomePA：用于reactome途径分析和可视化的R/Bioconductor软件包。摩尔生物系统。12477-479（2016）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Wickham, H. ggplot2: Elegant Graphics for Data Analysis https://ggplot2.tidyverse.org (2016).Győrffy, B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput. Struct. Biotechnol. J. 19, 4101–4109 (2021).Article .

Wickham，H.ggplot2：用于数据分析的优雅图形https://ggplot2.tidyverse.org（2016年）。Győrffy，B。整个转录组的生存分析确定了乳腺癌预后能力最高的生物标志物。计算机。结构。生物技术。J、 194101-4109（2021）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kassambara, A. ggpubr: ‘ggplot2’ Based Publication Ready Plots. https://cran.r-project.org/web/packages/ggpubr/index.html (2023).Download referencesAcknowledgementsThis study was supported by the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (A20221175) and Basic Science Research Programs through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning, Korea (NRF-2018R1D1A1B07048831).Author informationAuthor notesThese authors contributed equally: Su Min Cha, Jung-Wook Park, Yoon Jae Lee.Authors and AffiliationsDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South KoreaSu Min Cha, Gyungyub Gong, Hee Jin Lee & Byung-Kwan JeongBiomedical Sciences, Asan Medical Institute of Convergence Science and Technology (AMIST), University of Ulsan College of Medicine, Seoul, South KoreaSu Min Cha & Hee Jin LeeNeogenTC Corp., Seoul, South KoreaJung-Wook Park, Hee Jae Lee, Hyeonjin Lee, In Won Lee & Hee Jin LeeUniversity of Ulsan College of Medicine, Seoul, South KoreaYoon Jae LeeSchool of Systems Biomedical Science, Soongsil University, Seoul, Republic of KoreaSung Hee ParkAuthorsSu Min ChaView author publicationsYou can also search for this author in.

Kassambara，A。ggpubr：“基于ggplot2”的出版就绪图。https://cran.r-project.org/web/packages/ggpubr/index.html。下载参考文献致谢本研究得到了韩国首尔Asan医学中心Asan生命科学研究所（A20221175）和韩国国家研究基金会（NRF）的基础科学研究计划的支持，该基金会由韩国科学，ICT和未来规划部资助（NRF-2018R1D1A1B07048831）。作者信息作者注意到这些作者做出了同样的贡献：Su Min Cha，Jung Wook Park，Yoon Jae Lee。作者和附属机构蔚山大学医学院阿山医学中心病理学系，首尔，南韩闵察，庆玉宫，李希珍和Byung Kwan JeongBiomedical Sciences，蔚山大学医学院阿山医学融合科学与技术研究所（AMIST），首尔，南韩闵察和Hee-Jin LeeNeogenTC Corp.，首尔，南韩中宇公园，李希珍，李贤仁，李元元和李希珍蔚山大学医学院，首尔，南韩尹在利系统生物医学科学学院，宋西里大学韩国首尔市顺熙公园作者Su Min ChaView作者出版物您也可以在中搜索该作者。

PubMed Google ScholarJung-Wook ParkView author publicationsYou can also search for this author in

PubMed Google ScholarJung Wook ParkView作者出版物您也可以在

PubMed Google ScholarYoon Jae LeeView author publicationsYou can also search for this author in

PubMed Google ScholarYoon Jae LeeView作者出版物您也可以在

PubMed Google ScholarHee Jae LeeView author publicationsYou can also search for this author in

PubMed Google ScholarHee Jae LeeView作者出版物您也可以在

PubMed Google ScholarHyeonjin LeeView author publicationsYou can also search for this author in

PubMed Google ScholarHyeonjin LeeView作者出版物您也可以在

PubMed Google ScholarIn Won LeeView author publicationsYou can also search for this author in

PubMed Google ScholarIn Won LeeView作者出版物您也可以在

PubMed Google ScholarGyungyub GongView author publicationsYou can also search for this author in

PubMed Google ScholarGyungyub GongView作者出版物您也可以在

PubMed Google ScholarSung Hee ParkView author publicationsYou can also search for this author in

PubMed Google ScholarSung Hee ParkView作者出版物您也可以在

PubMed Google ScholarHee Jin LeeView author publicationsYou can also search for this author in

PubMed Google ScholarHee Jin LeeView作者出版物您也可以在

PubMed Google ScholarByung-Kwan JeongView author publicationsYou can also search for this author in

PubMed Google ScholarByung Kwan JeongView作者出版物您也可以在

PubMed Google ScholarContributionsS.M.C., J.-W.P., Y.J.L., B.-K.J., and H.Jin.L. were responsible for the study concept and design. S.M.C., J.-W.P., H.Jae.L., and H.Jin.L. were responsible for the acquisition of data, technical and material support. S.M.C., J.-W.P., B.-K.J., H.L, I.W.L., and H.Jin.L.

PubMed谷歌学术贡献。M、 。五十、 负责研究概念和设计。S、 M.C.，J.-W.P.，H.Jae。五十、 和H.Jin。五十、 负责获取数据、技术和物质支持。S、 M.C.，J.-W.P.，B.-K.J.，H.L，I.W.L。和H.Jin。L。

were responsible for the analysis and interpretation of data. S.M.C., Y.J.L., B.-K.J., and H.Jin.L. were responsible for the drafting of the manuscript. G.G. and S.H.P. were responsible for critical revision of the manuscript for important intellectual content. All authors have critically reviewed the paper and approved the final version.Corresponding authorsCorrespondence to.

负责数据的分析和解释。S、 M.C.，Y.J.L.，B.-K.J。和H.Jin。五十、 负责起草手稿。G、 G.和S.H.P.负责对重要知识内容的手稿进行严格修订。所有作者都对论文进行了批判性审查，并批准了最终版本。通讯作者通讯。

Hee Jin Lee or Byung-Kwan Jeong.Ethics declarations

李熙（Hee Jin Lee）或炳关正（Byung Kwan Jeong）。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationRights and permissions

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息权限

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

开放获取本文是根据知识共享署名非商业性NoDerivatives 4.0国际许可证授权的，该许可证允许以任何媒介或格式进行任何非商业性使用，共享，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出您是否修改了许可材料。

You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

根据本许可证，您无权共享源自本文或其部分的改编材料。本文中的图像或其他第三方材料包含在文章的知识共享许可证中，除非该材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不受法律法规的许可或超出许可用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by-nc-nd/4.0/..

Reprints and permissionsAbout this articleCite this articleCha, S.M., Park, JW., Lee, Y.J. et al. SPP1+ macrophages in HR+ breast cancer are associated with tumor-infiltrating lymphocytes.

转载和许可本文引用本文Cha，S.M.，Park，JW。，Lee，Y.J.等人，HR+乳腺癌中的SPP1+巨噬细胞与肿瘤浸润淋巴细胞有关。

npj Breast Cancer 10, 83 (2024). https://doi.org/10.1038/s41523-024-00695-7Download citationReceived: 18 January 2024Accepted: 22 September 2024Published: 30 September 2024DOI: https://doi.org/10.1038/s41523-024-00695-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

npj乳腺癌10,83（2024）。https://doi.org/10.1038/s41523-024-00695-7Download引文收到日期：2024年1月18日接受日期：2024年9月22日发布日期：2024年9月30日OI：https://doi.org/10.1038/s41523-024-00695-7Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供