PO.TB10.19 · 肿瘤生物学
疑似前列腺癌哥伦比亚男性的 TME 分析
TME profiling in Colombian men with suspected prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌（PCa）具有异质性的肿瘤微环境（TME），其塑造肿瘤演变和治疗应答。尽管免疫和基质组成已成为预后性生物标志物的来源，但在拉丁美洲人群中这些组分仍缺乏充分表征。此前尚无研究在此背景下将计算性免疫解卷积与原位验证相结合。我们旨在界定哥伦比亚队列中恶性、癌旁和良性前列腺组织间的 TME 重塑。对来自 75 例疑似 PCa 患者的 RNA-seq 数据进行 TMM 归一化，并使用针对 PSA、年龄和 Gleason 分级进行校正的差异表达模型进行分析。使用 CIBERSORT 和 xCell 推断免疫组成和基质富集。为进行验证，从 20 例前列腺切除术患者中构建了六个 TMA：五个 TMA 各包含三个 PCa 阳性病例（Gleason 分级 3+3、3+4、4+3、4+4、4+5），采样肿瘤和癌旁组织；一个 TMA 包含来自五个 PCa 阴性病例的良性组织。IHC 对 CD8⁺ T 细胞和 CD11b⁺ 髓系细胞浸润进行定量。解卷积揭示了恶性组织与良性组织间不同的免疫变化。PCa 阳性样本显示 M1 巨噬细胞（p=0.02）、浆细胞样树突状细胞（p<0.001）和 Th1 细胞（p=0.0075）显著富集，同时基质评分升高（p=0.0014），提示以炎症为主的 TME。相反，PCa 阴性样本显示更高的肥大细胞、造血干细胞、共同髓系祖细胞（均 p<0.0001）、NK 细胞（p=0.0009）、CD8⁺ 效应记忆 T 细胞（p=0.0006）和 CD4⁺ 初始 T 细胞（p=0.0047），与免疫静息状态一致。IHC 验证确认了肿瘤组织相比癌旁组织（p<0.001）和良性组织（p=0.016）的 CD8⁺ T 细胞浸润增加，以及相比癌旁组织（p=0.002）和良性组织（p=0.040）更高的 CD11b⁺ 髓系细胞浸润。关键的是，CD11b⁺ 浸润与 Gleason 分级相关，而 CD8⁺ 浸润在所有分级中均保持升高。本研究提供了哥伦比亚 PCa 队列中首个多模态 TME 分析。RNA-seq 解卷积与基于 TMA 的 IHC 的整合揭示了免疫重塑，其特征为恶性组织中细胞毒性 T 细胞和髓系群体的富集。分级依赖性的 CD11b⁺ 浸润提示其作为免疫治疗分层生物标志物的潜力，并支持在代表性不足的人群中对髓系细胞进行治疗性靶向。
查看英文原文 English abstract
Prostate cancer (PCa) features a heterogeneous tumor microenvironment (TME) that shapes evolution and therapeutic response. Although immune and stromal composition have emerged as source of prognostic biomarkers, these components remain poorly characterized in Latin American populations. No previous study has integrated computational immune deconvolution with in situ validation in this context. We aimed to define TME remodeling across malignant, adjacent, and benign prostate tissue in a Colombian cohort.RNA-seq data from 75 patients with suspected PCa were TMM-normalized and analyzed using differential expression models adjusted for PSA, age, and Gleason grade. Immune composition and stromal enrichment were inferred using CIBERSORT and xCell. For validation, six TMAs were constructed from 20 prostatectomy patients: five TMAs included three PCa-positive cases each (Gleason grades 3+3, 3+4, 4+3, 4+4, 4+5) sampling tumor and adjacent tissue, and one TMA contained benign tissue from five PCa-negative cases. IHC quantified CD8⁺ T-cell and CD11b⁺ myeloid infiltration.Deconvolution revealed distinct immune shifts between malignant and benign tissue. PCa-positive samples showed significant enrichment of M1 macrophages (p=0.02), plasmacytoid dendritic cells (p<0.001), and Th1 cells (p=0.0075), alongside elevated stromal scores (p=0.0014), indicating a predominantly inflammatory TME. In contrast, PCa-negative samples displayed higher mast cells, hematopoietic stem cells, common myeloid progenitors (all p<0.0001), NK cells (p=0.0009), CD8⁺ effector memory T cells (p=0.0006), and CD4⁺ naïve T cells (p=0.0047), consistent with an immunologically quiescent state. IHC validation confirmed increased CD8⁺ T-cell infiltration in tumor versus adjacent (p<0.001) and benign tissue (p=0.016), and higher CD11b⁺ myeloid infiltration versus adjacent (p=0.002) and benign tissue (p=0.040). Critically, CD11b⁺ infiltration correlated with Gleason grade, while CD8⁺ infiltration remained elevated across all grades.This study provides the first multimodal TME profiling in a Colombian PCa cohort. Integration of RNA-seq deconvolution with TMA-based IHC reveals immune remodeling characterized by enrichment of cytotoxic T cells and myeloid populations in malignant tissue. The grade-dependent CD11b⁺ infiltration suggests potential as a stratification biomarker for immunotherapy and supports therapeutic targeting of myeloid cells in underrepresented populations.
利益披露 Disclosure
D. M. Rodríguez Hernández, None..
J. Zabaleta, None..
L. Valle, None..
R. Parra-Medina, None..
C. L. Roa, None..
A. Gutierrez, None..
M. Barros Barraza, None..
A. Cómbita, None.