Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Nat Commun. 2023 Jan 6;14(1):98. doi: 10.1038/s41467-022-35238-w.
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.
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。