PO.PS01.09 · 人群科学

肯尼亚乳腺癌女性乳腺肿瘤免疫微环境的肿瘤与宿主决定因素

Tumor and Host Determinants of the Breast Tumor Immune Microenvironment in Kenyan Breast Cancer Women

编号 7606 展板 26 时间 4/22 09:00–12:00 区域 Section 35 主讲 Li (Cindy) Feng, BS;MS;PhD

分会场 Risk Prediction Modeling, Screening, Early Detection, and Preneoplastic and Tumor Markers

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作者与单位 Authors & Affiliations

Li Feng¹, Amber N. Hurson¹, Shahin Sayed², Hela Koka¹, Viviane Oluoch², Veronica Ngundo², Alfred Mburu Githuka², Zaitun Ajuoga², Shaoqi Fan¹, Kristine Jones³, Belynda Hicks³, Amy Hutchinson³, Maria Brown³, Petra Lenz³, Aaron M. Rozeboom³, Difei Wang³, Francis Makokha⁴, Stefan Ambs⁵, Jonine D. Figueroa¹, Ruth M. Pfeiffer¹, Xiaohong Rose Yang¹

¹Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD,²Aga Khan University Hospital, Nairobi, Kenya,³Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD,⁴Mount Kenya University, Nairobi, Kenya,⁵Center for Cancer Research, National Cancer Institute, Bethesda, MD

摘要 Abstract

中文摘要

背景：肿瘤免疫微环境（TIME）既反映肿瘤内在生物学特性，也反映宿主可调节因素。阐明肿瘤特征、体质指数（BMI）和生育史如何与免疫活性相关，可能有助于解释乳腺癌的异质性，并为精准预防和生存策略提供参考。方法：我们使用定制的NanoString nCounter®免疫聚焦基因面板分析了461例肯尼亚患者的浸润性乳腺肿瘤。采用PAM50进行内在亚型分型，并通过CIBERSORTx估计免疫细胞组成（22种免疫细胞的相对比例）。推导出复合免疫活性评分以代表功能模块：来自CIBERSORTx的z_hot（CD8+、M1巨噬细胞、活化NK细胞、滤泡辅助性T细胞）和z_suppression（Treg + M2巨噬细胞）；来自GSVA特征的z_cytotoxic（GZMB、PRF1）、z_exhaustion（PDCD1、LAG3、CTLA4）和z_checkpoint（PDCD1、PDCD1LG2、CTLA4、LAG3）。采用年龄校正的线性回归模型评估免疫评分与肿瘤特征（PAM50亚型、复发风险（ROR）、基于RNA的TP53状态、肿瘤分级）或宿主因素（BMI、绝经状态、产次、母乳喂养）之间的关联。在校正肿瘤特征和生活方式协变量的多变量回归模型中进一步检验了宿主因素的独立效应。使用错误发现率校正的p值处理多重检验。结果：参与者平均年龄50.3岁；43.8%的肿瘤为luminal A型，21.5%为基底样型。大多数女性超重/肥胖（BMI ≥ 25，73.1%），65.7%有≥3个孩子。高级别、基底样、高ROR和TP53突变样肿瘤显示出z_hot、z_cytotoxic、z_checkpoint和z_exhaustion评分升高的强有力证据（BH校正p < 0.001），同时基底样和TP53突变样肿瘤的z_suppression略有降低（p < 0.05），表明侵袭性肿瘤具有活跃TIME的特征。相比之下，已确立的乳腺癌危险因素对TIME的影响较弱。超重/肥胖患者更可能具有冷TIME（较低的CD8（p = 0.09）、滤泡辅助性T细胞（p < 0.05）和z_hot评分（p < 0.05）），而母乳喂养时间较长的患者具有更活跃的TIME（较高的滤泡辅助性T细胞和z_cytotoxicity；较低的M2巨噬细胞和z_suppression（所有p < 0.05））。结论：肿瘤内在亚型分类仍是免疫异质性的主要决定因素，而已确立的乳腺癌危险因素（BMI和生育危险因素）可能调节免疫反应性。整合肿瘤、生育和生活方式数据有助于阐明不同人群间的免疫变异。

查看英文原文 English abstract

Background: The tumor immune microenvironment (TIME) reflects both tumor-intrinsic biology and host-modifiable factors. Characterizing how tumor features, body mass index (BMI), and reproductive history relate to immune activity may help explain heterogeneity in breast cancer and inform precision prevention and survivorship strategies. Methods: We analyzed 461 invasive breast tumors from Kenyan patients using a custom NanoString nCounter® immune-focused gene panel. Intrinsic subtypes were assigned with PAM50, and immune cell composition (relative proportions for 22 immune cells) was estimated by CIBERSORTx. Composite immune activity scores were derived to represent functional modules: z_hot (CD8+, M1 macrophages, NK activated, T follicular helper) and z_suppression (Treg + M2 macrophages) from CIBERSORTx; z_cytotoxic (GZMB, PRF1) , z_exhaustion (PDCD1, LAG3, CTLA4) , and z_checkpoint ( PDCD1, PDCD1LG2, CTLA4, LAG3 ) from GSVA signatures. Associations between immune scores and tumor features (PAM50 subtypes, risk of recurrence (ROR), RNA-based TP53 status, tumor grade) or host factors (BMI, menopausal status, parity, breastfeeding) were evaluated in age-adjusted linear regression models. Independent effects of host factors were further examined in multivariable regression models adjusted for tumor characteristics and lifestyle covariates. Multiple testing was accommodated using a false discovery rate adjusted p -values. Results: Participants had a mean age of 50.3 years; 43.8% of tumors were luminal A and 21.5% basal-like. Most women were overweight/obese (BMI ≥ 25, 73.1%) and 65.7% had ≥ 3 children. High-grade, basal-like, high-ROR, and TP53 mutant-like tumors showed strong evidence of elevated z_hot , z_cytotoxic , z_checkpoint , and z_exhaustion scores (BH-adjusted p < 0.001), along with modestly lower z_suppression in basal-like and TP53 mutant-like tumors ( p < 0.05), indicating an active TIME characteristic of aggressive tumors. In contrast, established BC risk factors showed weaker influence on TIME. Overweight/obese patients were more likely to have cold TIME (lower CD8 ( p = 0.09), T follicular helper ( p < 0.05), and z_hot score ( p < 0.05)), while patients with longer duration of breastfeeding had more active TIME (higher T follicular helper and z_cytotoxicity; lower M2 macrophages and z_suppression (all p < 0.05)). Conclusions: Tumor-intrinsic subtype classification remains the dominant determinant of immune heterogeneity, while established BC risk factors (BMI and reproductive risk factors) may modulate immune responsiveness. Integrating tumor, reproductive, and lifestyle data can help clarify immune variation across diverse populations.

利益披露 Disclosure

L. Feng, None.. A. N. Hurson, None.. S. Sayed, None.. H. Koka, None.. V. Oluoch, None.. V. Ngundo, None.. A. Githuka, None.. Z. Ajuoga, None.. S. Fan, None.. K. Jones, None.. B. Hicks, None.. A. Hutchinson, None.. M. Brown, None.. P. Lenz, None.. A. M. Rozeboom, None.. D. Wang, None.. F. Makokha, None.. S. Ambs, None.. J. D. Figueroa, None.. R. M. Pfeiffer, None.. X. R. Yang, None.

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