PO.ET05.03 · 实验与分子治疗

乳腺肿瘤的纵向单细胞图谱揭示对芳香化酶抑制剂敏感和耐药的免疫及表观遗传机制

Longitudinal single-cell profiling of breast tumors reveals immune and epigenetic mechanisms of sensitivity and resistance to aromatase inhibitors

编号 7169 展板 1 时间 4/22 09:00–12:00 区域 Section 16 主讲 Xavier Tekpli, PhD

分会场 Role of the Microenvironment in Therapeutic Response

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作者与单位 Authors & Affiliations

Ilayda Altinönder¹, Villads Winton¹, Quy Khang Le², Marie Fongaard¹, Paal M. Bjornstad³, Elin Edda Seland Agustsdottir⁴, Stephanie Geisler⁵, Kamilla Fjermeros⁵, Manouchehr Seyedzadeh⁶, Unn-Cathrin Buvarp⁵, Marianne Lyngra⁷, Arnoldo Frigessi⁸, Diether Lambrechts⁹, Vessela N. Kristensen³, Anthony Mathelier⁸, Victor Greiff², Jürgen Geisler⁵, Xavier Tekpli¹

¹Department of Pathology, Oslo University Hospital, Oslo, Norway,²Department of Immunology, Oslo University Hospital, Oslo, Norway,³Department of Medical Genetics, Oslo University Hospital, Oslo, Norway,⁴Department of Breast and Endocrine Surgery, Akershus University Hospital, Oslo, Norway,⁵Department of Oncology, Akershus University Hospital, Oslo, Norway,⁶Department of Radiology, Akershus University Hospital, Oslo, Norway,⁷Department of Pathology, Akershus University Hospital, Oslo, Norway,⁸University of Oslo, Oslo, Norway,⁹KU Leuven, Leuven, Belgium

摘要 Abstract

中文摘要

背景。像letrozole和exemestane这样的芳香化酶抑制剂在雌激素受体（ER）阳性乳腺癌所有疾病阶段的治疗方案中发挥关键作用。然而，对此类疗法的耐药尚未被完全理解，仍是一项重大的临床挑战。方法。为研究ER阳性HER2阴性乳腺癌对芳香化酶抑制剂敏感和耐药的机制，我们对新辅助治疗前及治疗期间获取的肿瘤活检组织进行了单细胞RNA（scRNA-seq）、T细胞受体（scTCR-seq）和B细胞受体（scBCR-seq）测序，新辅助治疗为按随机顺序给予的letrozole和exemestane，持续6个月。结果。我们检查了来自73份生物标本的472,737个单细胞，这些标本采集于基线（n=25）、治疗中期（n=24）和新辅助治疗结束时（n=24）。我们在单细胞水平鉴定了转录起始位点的使用情况，以研究增强子活性在治疗压力下乳腺肿瘤演变中的作用。对治疗敏感的恶性细胞表现出升高的ER信号传导以及含ER结合位点的增强子中活性增加。相反，耐药的恶性细胞显示雄激素受体（AR）信号上调、细胞去分化以及神经内分泌样特征。在无应答者中AR顺式调控组的活性在治疗下增加，提示表观遗传修饰在治疗耐药中的作用。初治的肿瘤微环境可预测应答。无应答者表现出高比例的初始淋巴样细胞和未分化髓样细胞，提示无效的免疫格局。相反，应答者的特征为T细胞的克隆扩增。结论。综上所述，我们的纵向单细胞分析勾勒出驱动ER阳性乳腺癌对芳香化酶抑制剂敏感和耐药的遗传、表观遗传和细胞机制，为改进治疗策略开辟了途径。脚注。Ilayda Altinönder和Villads Winton为共同第一作者。Jürgen Geisler、Xavier Tekpli共同指导了本项工作。

查看英文原文 English abstract

Background. Aromatase inhibitors like letrozole and exemestane play a pivotal role in the treatment algorithms for estrogen receptor (ER) positive breast cancer in all phases of the disease. However, resistance to such therapies is not fully understood and remains a major clinical challenge. Methods. To investigate the mechanisms of sensitivity and resistance to aromatase inhibitors in ER-positive HER2-negative breast cancer, we conducted single-cell RNA (scRNA-seq), T cell receptor (scTCR-seq), and B cell receptor (scBCR-seq) sequencing on tumor biopsies obtained before and during neoadjuvant therapy with letrozole and exemestane given in a randomized sequence for 6 months. Results. We examined 472,737 single cells from 73 biospecimens collected at baseline (n=25), at mid-therapy (n=24) and at the end of neoadjuvant treatment (n=24). We identified transcription start site usage at single cell level to study the role of enhancer activity in the evolution of breast tumors under treatment pressure. Malignant cells that were sensitive to treatment exhibited elevated ER-signaling and increased activity in enhancers containing ER binding sites. Conversely, resistant malignant cells showed upregulated androgen receptor (AR) signaling, cellular de-differentiation, and neuroendocrine-like characteristics. The activity of AR cis-regulome increased under treatment in non-responders, suggesting a role of epigenetic modifications in treatment resistance. Treatment-naïve tumor microenvironment was predictive of response. Non-responders displayed high proportions of naive lymphoid and undifferentiated myeloid cells, indicating an ineffective immune landscape. In contrast, responders were characterized by clonal expansion of T cells. Conclusions. Taken together our longitudinal single-cell analyses delineate the genetic, epigenetic and cellular mechanisms that drive sensitivity and resistance to aromatase inhibitors in ER positive breast cancer, opening avenues for improved treatment strategies. Footnotes. Ilayda Altinönder and Villads Winton are shared first authors. Jürgen Geisler, Xavier Tekpli have jointly supervised this work.

利益披露 Disclosure

I. Altinönder, None.. V. Winton, None.. Q. K. Le, None.. M. Fongaard, None.. P. M. Bjornstad, None.. E. S. Agustsdottir, None.. S. Geisler, None.. K. Fjermeros, None.. M. Seyedzadeh, None.. U. Buvarp, None.. M. Lyngra, None.. A. Frigessi, None.. D. Lambrechts, None.. V. N. Kristensen, None.. A. Mathelier, None.. V. Greiff, None.. J. Geisler, None.. X. Tekpli, None.

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