PO.BCS01.02 · 生物信息与计算
应激反应性糖皮质激素受体信号塑造肺癌的免疫肿瘤微环境
Stress-responsive glucocorticoid receptor signaling shapes the immune tumor microenvironment in lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：肺癌中的种族差异持续存在，而黑人吸烟往往少于白人，提示可能存在其他因素导致肺癌风险。我们既往的研究表明，包括社区暴力犯罪在内的社会应激源可通过应激反应性机制塑造肿瘤生物学特征。在本研究中，我们探讨了社区暴力犯罪如何影响肿瘤微环境，重点关注糖皮质激素受体活性如何影响作为热免疫表型和冷免疫表型指标的M2巨噬细胞与CD8⁺ T细胞的空间分布模式。
方法：我们分析了15个肺肿瘤空间转录组样本，使用基因集共调控分析（GESECA）量化通路活性和细胞类型关联。空间共定位采用单变量和双变量局部Moran's I评估（p < 0.05）。为了超越Visium点尺寸提升空间分辨率，我们使用非负矩阵分解（NMF）提取潜在空间特征，估计经验变异函数以表征空间自相关，并应用普通克里金插值生成高分辨率空间图谱。
结果：社区暴力犯罪率与糖皮质激素受体活性呈正相关，表现为参与糖皮质激素生物合成通路活性的基因高表达（p < 0.05）。糖皮质激素受体活性升高的区域也显示出更高的上皮细胞丰度，尤其是在来自高犯罪社区的肿瘤中。高分辨率空间图谱进一步揭示，来自高暴力犯罪社区的肿瘤表现出M2巨噬细胞与CD8⁺ T细胞之间强烈的共定位，提示CD8⁺ T细胞被免疫抑制性髓系细胞包围，形成了功能上的“冷”肿瘤微环境。相反，来自低暴力犯罪社区的肿瘤显示出M2巨噬细胞与CD8⁺ T细胞更为相互排斥的空间模式，反映出“热”肿瘤微环境。
结论：我们的研究结果提示，暴露于社会应激源（如社区暴力犯罪）可能通过改变应激反应性通路和重塑免疫空间架构来影响肿瘤生物学特征。截然不同的热、冷免疫微环境可能提示不同社区背景下治疗效果的差异，从而可能加剧肺癌的差异。应根据免疫肿瘤微环境采用不同的免疫治疗策略以提高治疗效果。
查看英文原文 English abstract
Background: Racial disparities continue to exist in lung cancer, while Black individuals tend to smoke less than Whites, indicating potentially additional factors contribute to lung cancer risk. Our previous work showed that social stressors, including neighborhood violent crime, can shape tumor biology via stress-responsive mechanisms. In this study, we investigated how neighborhood violent crime influences tumor microenvironment with a focus on how glucocorticoid receptor activity impacts the spatial pattern of M2 macrophages and CD8⁺ T cells as indicators of hot and cold immune phenotypes.
Methods: We analyzed 15 lung tumor spatial transcriptomic samples to quantify pathway activity and cell type associations using gene set co-regulation analysis (GESECA). Spatial co-localization was assessed using univariate and bivariate local Moran's I (p < 0.05). To enhance spatial resolution beyond the Visium spot size, we extracted latent spatial features using non-negative matrix factorization (NMF), estimated empirical variograms to characterize spatial autocorrelation, and applied ordinary kriging to generate high-resolution spatial maps.
Results: Neighborhood violent crime rates were positively correlated with glucocorticoid receptor activity, as evidenced by high expression of genes involved in the glucocorticoid biosynthesis pathway activity (p < 0.05). Regions with elevated glucocorticoid receptor activity also showed higher abundance of epithelial cells, especially in tumors from high-crime neighborhoods. High-resolution spatial maps further revealed that tumors from high-violent crime neighborhoods displayed strong co-localization between M2 macrophages and CD8⁺ T cells, suggesting that CD8⁺ T cells are surrounded by immunosuppressive myeloid cells, creating a functionally “cold” tumor microenvironment. In contrast, tumors from low-violent crime neighborhoods showed more mutually exclusive spatial patterns of M2 macrophages and CD8⁺ T cells, reflecting a “hot” tumor microenvironment.
Conclusions: Our findings suggest that exposure to social stressors, such as neighborhood violent crime, may influence tumor biology by altering stress-responsive pathways and reshaping immune spatial architecture. The distinct hot and cold immune microenvironment may indicate differential treatment effectiveness across neighborhood contexts, potentially contributing to lung cancer disparities. Different immunotherapy strategies depending on immune tumor microenvironment to improve treatment effectiveness.
利益披露 Disclosure
S. Akter, None..
A. Soliman, None..
Z. Madak-Erdogan, None..
S. J. Kim, None.