Breast Tumor Microenvironment in Black Women: A Distinct Signature of CD8+ T-Cell Exhaustion
Breast Tumor Microenvironment in Black Women: A Distinct Signature of CD8+ T-Cell Exhaustion
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DOI：
10.1093/jnci/djaa215
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发表时间：
2021-01-05
影响因子：
10.3
通讯作者：
Ambrosone, Christine B.
中科院分区：
文献类型：
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作者：
Yao, Song;Cheng, Ting-Yuan David;Ambrosone, Christine B.
背景：黑人往往比白人有更强的炎症免疫反应。我们假设，宿主免疫的种族差异也表现在肿瘤微环境中，构成了黑人女性死亡率较高的独特侵略性肿瘤生物学的一部分。研究方法：病理学和基因表达谱分析方法用于表征来自妇女健康研究圈的1315名患者的乳腺肿瘤微环境中的浸润性免疫细胞。比较了肿瘤免疫表型的种族差异，结果在公开数据集中得到验证。在3个独立队列中评估免疫表型的预后相关性。结果：我们发现黑人和白色患者之间的肿瘤免疫反应存在显著且一致的差异。黑人的肿瘤不仅表现出更强的整体免疫存在，而且免疫浸润的组成和质量也不同，无论肿瘤亚型如何。黑人患者有更强的CD 4（+）和B细胞反应，而且，更疲惫的CD 8（+）T细胞谱。一个特征表明耗尽的CD 8（+）T细胞与总CD 8（+）T细胞（ExCD 8-r）的比率较高，这与生存率较低相关，特别是在激素受体阳性患者中。在激素受体阴性患者中，CD 8（+）T细胞的绝对分数和ExCD 8-r特征的组合确定了CD 8（低）ExCD 8-r（高）亚组，在黑人中最普遍，生存率最差。结论：我们在黑人乳腺癌患者中发现了一个明显的耗尽的CD 8（+）T细胞特征，这表明了他们更具侵袭性的疾病的免疫生物学基础，以及使用免疫检查点抑制剂靶向耗尽表型的理由。
Background: Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment, constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women. Methods: Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast tumor microenvironment from 1315 patients from the Women's Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in 3 independent cohorts. Results: We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence but also the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4(+) and B-cell response, and further, a more exhausted CD8(+) T-cell profile. A signature indicating a higher ratio of exhausted CD8(+) T cells to total CD8(+) T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor-positive patients. Among hormone receptor-negative patients, combinations of the absolute fraction of CD8(+) T cells and ExCD8-r signature identified the CD8(low)ExCD8-r(high) subgroup, the most prevalent among Blacks, with the worst survival. Conclusions: Our findings of a distinct exhausted CD8(+) T-cell signature in Black breast cancer patients indicate an immunobiological basis for their more aggressive disease and a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.