PO.IM02.05 · 免疫学
非甾体抗炎药、对乙酰氨基酚的使用与乳腺肿瘤的体细胞免疫特征
Use of non-steroidal anti-inflammatory drugs, acetaminophen and somatic immune profiles in breast tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景。肿瘤浸润淋巴细胞（TILs）是包括乳腺癌在内的多种癌症的预后生物标志物。TILs的富集可能有助于识别高度免疫原性和免疫脆弱的肿瘤，这些肿瘤可能对免疫介导的机制更具反应性并与改善的预后相关。近期数据提示对乙酰氨基酚的使用可能具有免疫抑制作用。在本研究中，我们在一项基于人群的前瞻性队列研究中，调查了常用镇痛药的使用与乳腺肿瘤免疫特征之间的关系。
方法。本分析在纳入癌症预防研究3（2006-2013）的浸润性乳腺癌女性中进行。在入组时和随访调查（2015年和2019年）时评估非甾体抗炎药（NSAIDs）和对乙酰氨基酚的使用。镇痛药信息来自癌症诊断之前但时间上最接近的调查。合格患者需具有可用的福尔马林固定石蜡包埋乳腺肿瘤样本。使用先前发表的方法从肿瘤RNA生成免疫特征，以从乳腺肿瘤中导出十个免疫细胞类型特异性评分加上一个细胞毒性细胞评分。使用线性回归估计每种镇痛药使用与免疫评分之间的关联，并对诊断年龄、分期和雌激素受体（ER）状态进行校正。使用假发现率（FDR）处理多重检验，FDR<0.05视为具有统计学意义。
结果。本分析纳入887例乳腺癌患者，诊断时中位年龄58岁（四分位距：51，63）。诊断时，大多数女性为绝经后（61%），肿瘤为ER阳性（80%）且为局限性疾病（65%）。在纳入分析的乳腺癌幸存者中，450例（51%）报告使用NSAID，137例（15%）报告使用对乙酰氨基酚。报告使用NSAID的患者与非使用者具有相似的免疫特征（FDR>0.05）。然而，与非使用者相比，对乙酰氨基酚使用者的T细胞、辅助性T细胞、Treg细胞、自然杀伤（NK）细胞、中性粒细胞、嗜酸性粒细胞和细胞毒性T细胞评分更低（FDR<0.05）。ER阳性肿瘤患者的结果与整体结果相似，例外之处是对乙酰氨基酚使用者的CD8+ T细胞评分也显著更低（FDR<0.05）。在ER阴性肿瘤女性中，NSAID使用者与非使用者之间的免疫特征没有差异。与非使用者相比，仅有NK细胞、中性粒细胞和嗜酸性粒细胞评分在对乙酰氨基酚使用者中显著更低（FDR<0.05）。
结论。NSAID的使用似乎不影响乳腺肿瘤免疫微环境。相比之下，我们观察到对乙酰氨基酚的使用降低了多种免疫细胞类型的评分，包括那些与改善预后相关的细胞类型。
查看英文原文 English abstract
Background. Tumor-infiltrating lymphocytes (TILs) represent a prognostic biomarker in several cancers, including breast cancer. Enrichment of TILs may help to identify highly immunogenic and immune-vulnerable tumors that may be more responsive to immune-mediated mechanisms and are associated with improved outcomes. Recent data suggest that the use of acetaminophen may have immunosuppressive effects. In this study, we investigated the relationship between the use of common analgesics and immune profiles in breast tumors from patients within a population-based prospective cohort study.
Methods. This analysis was conducted among females with invasive breast cancer enrolled in the Cancer Prevention Study 3 (2006-2013). Use of non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen was assessed at enrollment and follow-up surveys (2015 and 2019). Analgesic information came from the survey prior to, but closest in time to, their cancer diagnosis. Eligible patients were required to have formalin-fixed paraffin-embedded breast tumor samples available. Immune profiles were generated from tumor RNA using a previously published method to derive ten immune cell-type-specific scores plus a cytotoxic cell score from breast tumors. Linear regression was used to estimate the associations between each type of analgesic use and the immune scores, adjusting for age at diagnosis, stage, and estrogen receptor (ER) status. Multiple testing was addressed using the false discovery rate (FDR), with FDR<0.05 considered statistically significant.
Results. This analysis included 887 breast cancer patients with a median age at diagnosis of 58 years (interquartile range: 51, 63). At the time of diagnosis, most of the women were post-menopausal (61%), had ER positive tumors (80%) and localized disease (65%). Among the breast cancer survivors included in the analysis, 450 (51%) reported NSAID use and 137 (15%) acetaminophen use. Patients who reported use of NSAID had similar immune profiles to non-users (FDR>0.05). However, acetaminophen users had lower scores for T-cells, T helper cells, Treg cells, natural killer (NK) cells, neutrophils, eosinophils and cytotoxic T cells compared with non-users (FDR<0.05). Results among patients with ER-positive tumors were similar to the overall results with the exception that the CD8+ T cell score was also significantly lower among acetaminophen users (FDR<0.05). Among women with ER-negative tumors, there was no difference in immune profiles between NSAID users and non-users. Only NK cell, neutrophil, and eosinophil scores were significantly lower among acetaminophen users compared with non-users (FDR<0.05).
Conclusions. NSAID use does not appear to influence the breast tumor immune microenvironment. In contrast, we observed that acetaminophen use lowers the scores of multiple immune cell types, including those related to improved prognosis.
利益披露 Disclosure
C. Bodelon, None.