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人类乳腺癌中 T 细胞耗竭相关免疫环境的全面单细胞图谱

A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer.

机构信息

Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.

Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

出版信息

Nat Commun. 2023 Jan 6;14(1):98. doi: 10.1038/s41467-022-35238-w.

Abstract

Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1 exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I - but not PD-L1 - on tumor cells are strong distinguishing features between these environments.

摘要

在乳腺癌中,免疫检查点疗法仍然仅限于三阴性患者,且长期临床获益较为罕见。免疫检查点阻断的主要目的是防止或逆转耗竭 T 细胞状态,但乳腺癌肿瘤中的 T 细胞耗竭尚未得到充分理解。在这里,我们使用单细胞转录组学结合成像质谱细胞术,系统地研究了含有或不含有耗竭 T 细胞的人类乳腺癌肿瘤的免疫环境,重点关注腔型亚型。我们发现,存在 PD-1 耗竭样 T 细胞表型与具有特征性细胞毒性特征的炎症性免疫环境相关,髓样细胞激活增加,表明存在上调的免疫调节、趋化和细胞因子信号,以及自然杀伤 T 细胞的积累。具有耗竭样 T 细胞的肿瘤表现出肿瘤细胞上 MHC-I 表达增加,T 细胞上 CXCL13 表达增加,以及更不成熟而不是成熟的三级淋巴样结构的空间组织改变。我们的数据揭示了腔型乳腺癌中存在耗竭 T 细胞和不存在耗竭 T 细胞的免疫环境之间的根本差异,并表明 T 细胞上的 PD-1 和 CXCL13 以及肿瘤细胞上的 MHC-I——而非 PD-L1——是这些环境之间的强区别特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cff/9822999/3238d6501c6c/41467_2022_35238_Fig1_HTML.jpg

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