Department of Immuno-Oncology, Beckman Research Institute.
Light Microscopy Digital Imaging Core, Beckman Research Institute.
JCI Insight. 2022 Feb 8;7(3):e153963. doi: 10.1172/jci.insight.153963.
CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling-related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.
CD8+ 肿瘤浸润淋巴细胞(TILs)与三阴性乳腺癌(TNBC)的生存改善相关,但与雌激素受体阳性(ER+)BC 的生存无关。这些对比发现的基础仍然难以捉摸。我们确定了浸润 CD8+ T 细胞的 BC 肿瘤亚群,这些细胞具有耗尽 T 细胞(TEX)的特征。富含 CD8+TEX 的肿瘤表现出独特的肿瘤微环境,其特征是干扰素-γ 信号相关途径的扩增和程序性死亡配体 1 表达增加。矛盾的是,较高水平的肿瘤浸润 CD8+TEX 与 ER+BC 患者的总生存期降低相关,但与 TNBC 患者无关。此外,肿瘤中 CD8+TEX 特征的高表达与 ER+BC 绝经前患者的生存率明显降低有关,但与绝经后患者无关。最后,我们证明了肿瘤 TEX 特征评分在识别 Oncotype DX 乳腺复发评分中等的 ER+BC 绝经前高危患者中的价值。我们的数据强调了 CD8+TILs、干扰素-γ 信号和 ER 状态在 BC 患者生存中的复杂关系。这项工作确定了肿瘤浸润性 CD8+TEX 是 ER+BC 绝经前早期患者生存结局降低的关键特征。