Kuett Laura, Bollhagen Alina, Tietscher Sandra, Sobottka Bettina, Eling Nils, Varga Zsuzsanna, Moch Holger, de Souza Natalie, Bodenmiller Bernd
Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Cancer Res. 2025 Jan 2;85(1):15-31. doi: 10.1158/0008-5472.CAN-24-1211.
Breast cancer is the most commonly diagnosed cancer in women, with distant metastasis being the main cause of breast cancer-related deaths. Elucidating the changes in the tumor and immune ecosystems that are associated with metastatic disease is essential to improve understanding and ultimately treatment of metastasis. Here, we developed an in-depth, spatially resolved single-cell atlas of the phenotypic diversity of tumor and immune cells in primary human breast tumors and matched distant metastases, using imaging mass cytometry to analyze a total of 75 unique antibody targets. Although the same tumor cell phenotypes were typically present in primary tumors and metastatic sites, suggesting a strong founder effect of the primary tumor, their proportions varied between matched samples. Notably, the metastatic site did not influence tumor phenotype composition, except for the brain. Metastatic sites exhibited a lower number of immune cells overall but had a higher proportion of myeloid cells as well as exhausted and cytotoxic T cells. Myeloid cells showed distinct tissue-specific compositional signatures and increased presence of potentially matrix remodeling phenotypes in metastatic sites. This analysis of tumor and immune cell phenotypic composition of metastatic breast cancer highlights the heterogeneity of the disease within patients and across distant metastatic sites, indicating myeloid cells as the predominant immune modulators that could potentially be targeted at these sites. Significance: Multiplex imaging analysis of matched primary and metastatic breast tumors provides a phenotypic and spatial map of tumor microenvironments, revealing similar compositions of cancer cells and divergent immunologic features between matched samples.
乳腺癌是女性中最常被诊断出的癌症，远处转移是乳腺癌相关死亡的主要原因。阐明与转移性疾病相关的肿瘤和免疫生态系统的变化对于增进对转移的理解并最终改善转移治疗至关重要。在此，我们利用成像质谱流式细胞术分析总共75个独特的抗体靶点，构建了原发性人类乳腺肿瘤及配对远处转移灶中肿瘤和免疫细胞表型多样性的深度、空间分辨单细胞图谱。尽管原发性肿瘤和转移部位通常存在相同的肿瘤细胞表型，提示原发性肿瘤有很强的奠基者效应，但它们在配对样本中的比例有所不同。值得注意的是，除脑转移外，转移部位不影响肿瘤表型组成。转移部位总体免疫细胞数量较少，但髓系细胞以及耗竭和细胞毒性T细胞的比例较高。髓系细胞在转移部位呈现出独特的组织特异性组成特征，且具有潜在基质重塑表型的细胞数量增加。对转移性乳腺癌肿瘤和免疫细胞表型组成的这种分析突出了患者体内及不同远处转移部位疾病的异质性，表明髓系细胞是这些部位潜在的主要免疫调节因子，可作为靶向目标。意义：对配对的原发性和转移性乳腺肿瘤进行多重成像分析，提供了肿瘤微环境的表型和空间图谱，揭示了癌细胞组成相似但配对样本间免疫特征不同的情况。
