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外周血 TCR 克隆型多样性作为乳腺癌进展的年龄相关标志物。

Peripheral blood TCR clonotype diversity as an age-associated marker of breast cancer progression.

机构信息

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.

Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.

出版信息

Proc Natl Acad Sci U S A. 2023 Dec 5;120(49):e2316763120. doi: 10.1073/pnas.2316763120. Epub 2023 Nov 27.

Abstract

Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential associations between peripheral immunity and breast tumor progression, here, we assessed the peripheral blood TCR clonotype of 485 breast cancer patients diagnosed with either DCIS or de novo stage IV disease at younger (<45) or older (≥45) age. TCR clonotype diversity was significantly lower in older compared to younger breast cancer patients regardless of tumor stage at diagnosis. In the younger age group, TCR-α clonotype diversity was lower in patients diagnosed with de novo stage IV breast cancer compared to those diagnosed with DCIS. In the older age group, DCIS patients with higher TCR-α clonotype diversity were more likely to have a recurrence compared to those with lower diversity. Whole blood transcriptome profiles were distinct depending on the TCR-α Chao1 diversity score. There were more CD8 T cells and a more active immune environment in DCIS tumors of young patients with higher peripheral blood TCR-α Chao1 diversity than in those with lower diversity. These results provide insights into the role that host immunity plays in breast cancer development across different age groups.

摘要

免疫逃逸是肿瘤生长的前提。我们之前描述了浸润性乳腺癌与导管原位癌(DCIS)相比,肿瘤内激活的细胞毒性 T 细胞和 T 细胞受体(TCR)克隆型多样性下降,这意味着 T 细胞反应的减少在肿瘤进展中起着核心作用。为了确定外周免疫与乳腺肿瘤进展之间的潜在关联,在这里,我们评估了 485 名乳腺癌患者的外周血 TCR 克隆型,这些患者被诊断为 DCIS 或新发 IV 期疾病,年龄分别小于(<45)或大于(≥45)。无论诊断时的肿瘤分期如何,与年轻患者相比,老年患者的 TCR 克隆型多样性明显较低。在年轻组中,与诊断为 DCIS 的患者相比,诊断为新发 IV 期乳腺癌的患者 TCR-α 克隆型多样性较低。在老年组中,与多样性较低的患者相比,TCR-α 克隆型多样性较高的 DCIS 患者更有可能复发。全血转录组谱取决于 TCR-α Chao1 多样性评分。与多样性较低的患者相比,具有更高外周血 TCR-α Chao1 多样性的年轻患者的 DCIS 肿瘤中具有更多的 CD8 T 细胞和更活跃的免疫环境。这些结果提供了宿主免疫在不同年龄组乳腺癌发展中所起作用的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069d/10710020/601d1c423c62/pnas.2316763120fig01.jpg

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