PO.BCS01.03 · 生物信息与计算

雄激素受体表达与ER阳性/HER2阴性乳腺癌的免疫浸润及免疫检查点抑制剂应答呈负相关

Androgen receptor expression negatively correlates with immune infiltration and response to immune checkpoint inhibitors in ER-positive/HER2-negative breast cancer

编号 2684 展板 9 时间 4/20 02:00–05:00 区域 Section 1 主讲 Jun Arima, MD;PhD

分会场 Application of Bioinformatics to Cancer Biology 3

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作者与单位 Authors & Affiliations

Jun Arima¹, Kohei Chida², Rongrong Wu³, Takafumi Shima¹, Toru Kuramoto¹, Hiroki Hamamoto¹, Kohei Taniguchi⁴, Nao Kawaguchi¹, Ryo Tanaka¹, Yoshiro Imai¹, Kosei Kimura¹, Mitsuhiko Iwamoto¹, Kenichi Hakamada⁵, Takashi Ishikawa⁶, Sang-Woong Lee¹, Kazuaki Takabe²

¹Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan,²Roswell Park Comprehensive Cancer Center, Buffalo, NY,³Tokyo Medical University, Tokyo, Japan, Japan,⁴Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan,⁵Hirosaki University Graduate School of Medicine, Hirosaki, Japan,⁶Breast Surgery, Tokyo Medical University, Tokyo, Japan

摘要 Abstract

中文摘要

背景：AR在一部分三阴性乳腺癌（BC）中发挥关键作用，尤其是管腔雄激素受体（LAR）亚型，该亚型已知对化疗耐药。值得注意的是，在一项随机临床试验中，AR抑制剂enzalutamide提高了ER+/HER2- BC的病理完全缓解（pCR）率，尽管其潜在的生物学机制仍不清楚。早期研究表明，enzalutamide与ICIs联用治疗LAR-TNBC时具有初步的临床获益。基于这些临床发现，我们的研究探讨了AR表达如何影响肿瘤微环境（TME）并调节ICIs在ER+/HER2- BC中的疗效。方法：共分析了来自五个队列的4070例BC患者的整体肿瘤转录组数据（I-SPY2 [GSE173839]、TCGA、METABRIC、SCAN-B [GSE96058]、GSE271080 [NCT02955395]）以及两个单细胞转录组队列（GSE246613、GSE167036）。AR高表达定义为各队列中表达水平最高的三分之二。LAR-TNBC定义为TNBC/Basal亚型中AR表达最高的三分之二肿瘤。结果：在TCGA中，ER+/HER2- BC与LAR-TNBC相比表现出显著更低的基因组不稳定性水平。这种低基因组不稳定性与ER+/HER2-疾病特征性的免疫"冷"表型相一致。在ER+/HER2- BC中，AR表达在TCGA、METABRIC和SCAN-B队列中均与肿瘤浸润淋巴细胞（TILs）数量一致地呈负相关（均p < 0.05）。此外，在METABRIC和SCAN-B队列中，AR表达与CD8+ T细胞、树突状细胞（DCs）、M1巨噬细胞浸润减少相关（均p < 0.05）。而且，在I-SPY2试验中，高AR表达与ER+/HER2- BC新辅助ICI治疗后较低的pCR率相关（p=0.002）。单细胞转录组分析显示，AR不仅在上皮细胞中表达，还在多种基质和免疫细胞群中表达，包括成纤维细胞、T细胞和髓系细胞。值得注意的是，上皮细胞和内皮细胞中的AR表达与ICI应答呈负相关。通过分析NCT02955395试验队列，我们发现enzalutamide治疗显著增加了ER+/HER2- BC中CD8+ T细胞、DCs和M1巨噬细胞的浸润，与在AR低表达肿瘤中观察到的结果相似（均p < 0.05）。结论：我们发现AR表达与ER+/HER2- BC中的免疫和髓系细胞浸润以及ICI应答呈负相关。鉴于使用enzalutamide抑制AR可诱导出相似的免疫微环境特征，将ICIs与该治疗联合可能为ER+/HER2- BC提供临床获益。

查看英文原文 English abstract

Background: AR plays a pivotal role in a subset of triple-negative BC, particularly the luminal androgen receptor (LAR) subtype, which is known to be resistant to chemotherapy. Notably, enzalutamide, an AR inhibitor, improved the pathological complete response (pCR) rate in ER+/HER2- BC in a randomized clinical trial, although the underlying biological mechanisms remain unclear. Early-phase studies have implicated preliminary clinical benefit when enzalutamide was combined with ICIs in LAR-TNBC. Building on these clinical findings, our study investigated how AR expression affects the tumor microenvironment (TME) and modulates the efficacy of ICIs in ER+/HER2- BC. Methods: A total of 4070 BC patients from five cohorts with transcriptome of bulk tumors (I-SPY2 [GSE173839], TCGA, METABRIC, SCAN-B [GSE96058], GSE271080[NCT02955395]) and two cohorts with Single-cell transcriptome (GSE246613, GSE167036) were analyzed. High expression of AR was defined as the top two-thirds of expression levels for each cohort. LAR-TNBC was defined as the top two-thirds of AR-expressing tumors within the TNBC/Basal subtype. Results: ER+/HER2- BC exhibited substantially lower levels of genomic instability compared with LAR-TNBC in TCGA. This low genomic instability is consistent with the immunologically “cold” phenotype characteristic of ER+/HER2- disease.Among ER+/HER2- BC , AR expression was consistently and negatively associated with number of Tumor-Infiltrating Lymphocytes (TILs) consistently in the TCGA, METABRIC, and SCAN-B cohorts (all p < 0.05). Further, AR expression was associated with reduced infiltration of CD8+ T cells, dendritic cells (DCs), M1 macrophages in the METABRIC and SCAN-B cohorts (all p < 0.05). Moreover, high AR expression was associated with lower pCR rates after neoadjuvant ICI treatment in ER+/HER2- BC in the I-SPY2 trial (p=0.002). Single-cell transcriptomic analyses revealed that AR was expressed not only in epithelial cells but also in various stromal and immune cell populations, including fibroblasts, T cells, and myeloid cells. Notably, AR expression in epithelial and endothelial cells were inversely correlated with ICI response. Analyzing the NCT02955395 trial cohort, we found that enzalutamide treatment significantly increased the infiltration of CD8+ T cells, DCs, and M1 macrophages in ER+/HER2- BC, similar to that observed in AR-low tumors (all p < 0.05). Conclusion: We found that AR expression was inversely associated with immune and myeloid cell infiltration as well as ICI response in ER+/HER2- BC. Given that AR suppression with enzalutamide induced a similar immune microenvironmental profile, combining ICIs with this treatment may provide clinical benefit in ER+/HER2- BC.

利益披露 Disclosure

J. Arima, Medtronic Japan ). R. Wu, None.. T. Shima, None.. T. Kuramoto, None.. H. Hamamoto, None.. K. Taniguchi, None.. N. Kawaguchi, None.. R. Tanaka, None.. Y. Imai, None.. K. Kimura, None.. M. Iwamoto, None.. K. Hakamada, None.. S. Lee, None.

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